RU2652138C2 - Solid forms of fungicidal pyrazoles - Google Patents

Abstract

FIELD: agriculture.

SUBSTANCE: invention refers to agriculture. Polymorph of 4-(2-bromo-4-fluorophenyl)-N-(2-chloro-6-fluorophenyl)-1,3-dimethyl-1H-pyrazol-5-amine is proposed. To prepare the polymorph form B, a slurry is formed with a solvent of one or more solid forms 4-(2-bromo-4-fluorophenyl)-N-(2-chloro-6-fluorophenyl)-1,3-dimethyl-1H-pyrazole-5-amine, selected from the group of form A, amorphous forms and mixtures of any of the above, with form B and maintaining the slurry during the conversion of solid forms 4-(2-bromo-4-fluorophenyl)-N-(2-chloro-6-fluorophenyl)-1,3-dimethyl-1H-pyrazole-5-amine into polymorph B.

EFFECT: invention will increase the effectiveness of protecting plants and seeds from fungal infections.

16 cl, 2 dwg, 17 tbl

Description

FIELD OF THE INVENTION

The present invention relates to solid forms of 4- (2-bromo-4-fluorophenyl) - N - (2-chloro-6-fluorophenyl) -1,3-dimethyl-1 H -pyrazol-5-amine, their preparation, compositions and methods of use for protecting a plant or plant seed from diseases caused by fungal pathogens.

BACKGROUND OF THE INVENTION

The solid state of chemical compounds can be amorphous (i.e., there is no long-range order in the positions of the atoms) or crystalline (i.e. the atoms are arranged according to an orderly repeating structure). The expression “polymorph” refers to a particular crystalline form (ie, crystal lattice structure) of a chemical compound that can exist in more than one crystalline form in the solid state. Polymorphs can differ in their chemical and physical (i.e. physicochemical) properties, such as crystal shape, density, hardness, color, chemical stability, melting point, hygroscopicity, suspendibility, solubility and dissolution rate, as well as biological properties such as bioavailability, bioavailability and toxicity.

It remains impossible to predict physicochemical properties, such as melting point or solubility, for a crystalline form in which a chemical compound in a solid state can exist. In addition, it is not even possible to predict whether a compound in a solid state can be present in more than one crystalline form.

PCT Patent Publication WO 2012/031061 discloses 4- (2-bromo-4-fluorophenyl) - N - (2-chloro-6-fluorophenyl) -1,3-dimethyl-1 H -pyrazole-5-amine and methods for its preparation and the use of this compound to protect a plant or plant seed from diseases caused by fungal pathogens. New solid forms of this compound, their compositions and methods for their preparation and use have also been disclosed.

SUMMARY OF THE INVENTION

The present invention relates to solid forms of 4- (2-bromo-4-fluorophenyl) - N - (2-chloro-6-fluorophenyl) -1,3-dimethyl-1 H -pyrazol-5-amine (compound 1 ). In particular, the present invention relates to a polymorph of compound 1 , designated Form A, characterized by a powder X-ray diffraction pattern in Cu (Kα1) at room temperature having at least reflection positions at 2θ angles of 6.395, 12.668, 14.507, 14.99, 18.984, 22.23, 23.885, 24.919 and 26.34 degrees. The present invention also relates in particular to a polymorph of compound 1 , designated Form B, characterized by a powder X-ray diffraction pattern in Cu (Kα1) at room temperature having at least reflection positions at 2θ angles of 10.894, 15.361, 16.134, 17.718, 20.322, 24.285, 25.84, 27.54 and 29.449 degrees.

The present invention relates to methods for converting one solid form of compound 1 to polymorphic form B. More specifically, the present invention is directed to a method for producing a polymorph of compound 1, designated Form B, the method comprising forming with a solvent a suspension of one or more solid forms of compound 1 , selected from the group of form A, amorphous forms, and mixtures thereof with form B, and maintaining the suspension during the conversion of solid forms of compound 1 to polymorphic form B.

The present invention also relates to methods for preparing the polymorphic Form B of compound 1 , comprising (A) contacting 1- (2-bromo-4-fluorophenyl) -2-propanone and 1-chloro-3-fluoro-2-isothiocyanatobenzene in the presence of the first a solvent to form a reaction mixture containing a thioamide intermediate, (B) optionally isolating a thioamide intermediate, (C) contacting the thioamide intermediate with methyl hydrazine in the presence of a second solvent to form a reaction mixture containing her compound 1 , and (D) crystallization of compound 1 as a polymorphic form B.

The present invention also relates to a composition for protecting a plant or plant seed from diseases caused by fungal pathogens, comprising (a) a polymorphic Form B of compound 1 ; and (b) at least one additional component selected from the group consisting of surfactants, solid diluents, and liquid carriers.

The present invention also relates to a composition for protecting a plant or plant seed from diseases caused by fungal pathogens, comprising (a) a polymorphic Form B of compound 1 ; and (b) at least one other nematicide, insecticide and / or fungicide.

The present invention further relates to a method for protecting a plant or plant seed from diseases caused by fungal pathogens, comprising applying to the plant, or the seed, or the medium in which the plant or seed is located, a biologically effective amount of compound 1 , including the polymorphic form B.

BRIEF DESCRIPTION OF GRAPHIC MATERIALS

Figure 1A shows powder X-ray diffraction patterns in Cu (Kα1) at room temperature for polymorphic form A of compound 1 , showing the absolute intensity of X-rays in pulses plotted against the positions of the reflections at angles of 2θ in degrees. Figure 1B shows powder X-ray diffraction patterns in Cu-Kα1 at room temperature for the polymorphic form B of compound 1 , showing the absolute intensity of the x-rays in pulses plotted against the positions of the reflections at angles of 2θ in degrees.

DETAILED DESCRIPTION OF THE INVENTION

The expressions used herein are intended to include, include, include, include, include, have, include, include, characterize, or any other their options apply to non-exclusive inclusion, provided that any limitation is clearly indicated. For example, a composition, mixture, process or method that includes a list of elements is not necessarily limited to only these elements, but may include other elements not explicitly listed or inherent to such composition, mixture, process or method.

The transitional phrase “consisting of” excludes any unspecified element, step or ingredient. If the claim contains such a phrase, it will not allow the inclusion in the claim of materials other than those listed, with the exception of impurities usually associated with them. If the phrase “consisting of” appears in the distinctive part of the claims, and not immediately after the restrictive part, it limits only the element set forth in this distinctive part; however, other elements as a whole are not excluded from the claim.

The transitional phrase “essentially consisting of” is used to mean a composition or method comprising materials, steps, features, components or elements in addition to being literally disclosed, provided that these additional materials, steps, features, components or elements do not substantially affect the main (main) and new (new) characteristic (s) of the claimed invention. The expression “essentially consisting of” occupies an intermediate position between “comprising” and “consisting of”.

If the applicants have defined the present invention or part of it with a non-limiting expression such as “comprising”, it will be easy to understand that (unless otherwise indicated) the present description should be interpreted as also describing such an invention using the expressions “essentially consisting of” or “consisting of "

In addition, unless expressly stated otherwise, “or” refers to an inclusive “or”, and not to an exclusive “or”. For example, conditions A or B are satisfied by any of the following: A is true (or present), and B is erroneous (or not present), A is erroneous (or not present), and B is true (or present), and A and B are true ( or are present).

It is also understood that the singular number of an element or component of the present invention is non-limiting with respect to the number of cases (i.e., occurrence) of an element or component. Therefore, the singular should be understood as including one or at least one, and the singular form for an element or component also includes the plural, unless the singular is explicitly implied.

As set forth in this disclosure, the term “invertebrate pest” includes arthropods, gastropods, and nematodes of economic importance as pests. The expression “arthropod” includes insects, ticks, spiders, scorpions, sea-footed, two-legged, woodlice and symphyla. The expression “gastropod” includes snails, slugs and other representatives of Stylommatophora. The expression “nematode” refers to a living organism of the type Nematoda.

In the context of the present disclosure, “invertebrate pest control” means suppressing the development of invertebrate pests (including death, loss of nutrition and / or mating disturbance), and related expressions are defined in a similar way.

As set forth in the present disclosure and claims, a “plant” includes members of the Plantae kingdom, in particular seed plants (Spermatopsida) at all stages of life, including young plants (eg, germinating seeds from which seedlings develop) and mature, reproductive stages ( for example, plants that form flowers and seeds). Parts of plants include geotropic organs, usually growing beneath the surface of a growing medium, such as roots, tubers, bulbs, and corms, as well as organs growing above a growing medium, such as foliage (including stems and leaves), flowers, fruits, and seeds. Growing media include soil, liquid culture media, gel-like culture media or soil mixtures with peat, bark, sawdust, sand, pumice, perlite, vermiculite and other similar materials. As set forth herein, the term “seedling”, used either singly or in combination of words, means a young plant developing from a seed germ.

As set forth in the present disclosure, the expression “fungal pathogen” or “fungal plant pathogen” includes pathogens from the classes Basidiomycete, Ascomycete, Oomycete and Deuteromycete, which are causative agents of a wide range of plant diseases of economic importance that affect decorative, turf-forming, vegetable, field, cereals and fruit crops. In the context of the present disclosure, “protecting a plant from disease”, “controlling a plant disease” or “controlling a fungal pathogen” includes a preventive action (disruption of the fungal infection cycle, colonization, development of symptoms and spore formation) and / or therapeutic effect (suppression of colonization of plant tissues the owner).

The term “water miscible” in the context of “water miscible solvent” means a liquid solvent (including a mixture of solvent compounds) that is completely soluble in water (and water soluble in the solvent) in all proportions at ambient temperature (for example, reaction) containing a water miscible solvent. Methanol, ethanol, acetone and acetonitrile are examples of water miscible solvents.

In contrast, the expression “water-immiscible” in the context of a substance that is “water-immiscible organic compound”, “water-immiscible liquid component” or “water-immiscible liquid carrier” means that the substance is not soluble in water (and water is soluble in substance) in any proportions at appropriate temperatures (for formulated compositions at a temperature approximately equal to room temperature, for example, at approximately 20 ° C). As a rule, water-immiscible substances used as liquid carriers or other liquid components in formulated compositions have little solubility in water, and water has little solubility in water-immiscible substances. Often, the water solubility of water immiscible substances used in the composition is less than about 1%, or less than about 0.1%, or even less than about 0.01% by weight at about 20 ° C.

The expression “continuous liquid phase” in the context of liquid formulated compositions refers to a liquid phase formed with a liquid carrier. The continuous liquid phase provides a bulk liquid medium in which other components for the composition are dissolved, dispersed (like solid particles) or emulsified (like liquid drops). If the liquid carrier is aqueous (water optionally containing dissolved water-soluble compounds), then the liquid emulsifiable in the aqueous liquid carrier is formed using a water-immiscible liquid component.

As used in the present disclosure, the term “room temperature” refers to a temperature of from about 18 ° C to about 28 ° C.

The expression “polymorph” refers to a particular crystalline form (ie, crystal lattice structure) of a chemical compound that can exist in more than one crystalline form in the solid state.

Embodiments of the present invention include the following:

Embodiment 1. Polymorph 4- (2-bromo-4-fluorophenyl) - N - (2-chloro-6-fluorophenyl) -1,3-dimethyl-1 H -pyrazol-5-amine (compound 1 ), called form A in the summary of the invention and characterized by a powder X-ray diffraction pattern in Cu (Kα1) at room temperature having at least reflection positions at angles 2θ

2θ 2θ 6,395 22.23 12,668 23,885 14,507 24,919 14,99 26.34 18,984

Embodiment 2. Polymorph 4- (2-bromo-4-fluorophenyl) - N - (2-chloro-6-fluorophenyl) -1,3-dimethyl-1 H -pyrazol-5-amine (compound 1 ) called Form B in the brief description of the invention and characterized by a powder x-ray diffraction pattern in Cu (Kα1) at room temperature having at least reflection positions at angles 2θ

2θ 2θ 10,894 24,285 15,361 25.84 16,134 27.54 17,718 29,449 20,322

Embodiment 3. The method described in the summary of the invention for preparing the polymorphic Form B of the compound according to Embodiment 2 provides for the formation of a suspension of one or more solid forms of compound 1 selected from the group of Form A, amorphous forms and mixtures of any of the above with Form B and a solvent maintaining the slurry during the conversion of solid forms of compound 1 in polymorphic form V.

Embodiment 4. The method of Embodiment 3, wherein the solid form of compound 1 includes polymorphic form A.

Embodiment 5. The method of Embodiment 3 wherein the solid forms of compound 1 comprise a mixture of polymorphic form A and form B.

Embodiment 6. The method of any one of Embodiments 3-5, wherein the seed crystals of polymorphic form B of Embodiment 2 are added to the suspension.

Embodiment 7. The method according to any one of Embodiments 3-6, wherein the suspension is mixed.

Embodiment 8. The method according to any one of Embodiments 3-6, wherein the suspension is mixed and heated to a temperature of 30 ° C. to the boiling point of the solvent.

Embodiment 9. A method according to any one of embodiments 3-8, wherein the solvent includes one or more of water, a complex C _4- C ₈ ether, C _1- C ₄ alkanol, C _3- C ₈ ketone, C _4- C ₈ ether, C ₂ -C ₇ nitrile or aromatic C ₇ -C ₉ hydrocarbon.

Embodiment 10. The method of Embodiment 9, wherein the solvent includes one or more of water, butyl acetate, methanol, 1-propanol or toluene.

Embodiment 11. The method of Embodiment 10, wherein the solvent includes one or more of water or methanol.

Embodiment 12. A method for producing crystalline compound 1 described in a summary of the invention, comprising (A) contacting 1- (2-bromo-4-fluorophenyl) -2-propanone and 1-chloro-3-fluoro-2-isothiocyanatobenzene in the presence of the first solvent to form a reaction mixture containing a thioamide intermediate, (B) optionally isolating a thioamide intermediate, (C) contacting the thioamide intermediate with methyl hydrazine in the presence of a second solvent to form a reaction an ionic mixture containing compound 1 , and (D) crystallization of compound 1 as a polymorphic form B.

Embodiment 13. The method of Embodiment 12 wherein the thioamide intermediate is isolated in step (B).

Embodiment 14. The method of Embodiment 12 wherein the thioamide intermediate is not isolated in step (B).

Embodiment 15. A method according to any one of Embodiments 12-14, wherein the thioamide intermediate is α-acetyl-2-bromo- N - (2-chloro-6-fluorophenyl) -4-fluorobenzylethanethioamide.

Embodiment 16. A method according to any one of embodiments 12-15, wherein the solvent includes one or more of the complex C _4- C ₈ ether, C _1- C ₄ alkanol, C _3- C ₈ ketone, C _4- C ₈ ether, C ₂ -C ₇ nitrile or aromatic C ₇ -C ₉ hydrocarbon.

Embodiment 17. The method of Embodiment 16 wherein the first solvent comprises one or more of tetrahydrofuran or methyl tert- butyl ether.

Embodiment 18. The method according to any one of Embodiments 12-17, wherein the first solvent is cooled to a temperature of 0 ° C to 15 ° C.

Embodiment 19. A method according to any one of embodiments 12-18, wherein the second solvent comprises one or more of water, a complex C _4- C ₈ ether, C _1- C ₄ alkanol, C _3- C ₈ ketone, C _{4 -} C ₈ ether, C ₂ -C ₇ nitrile or aromatic C ₇ -C ₉ hydrocarbon.

Embodiment 20. The method of Embodiment 19 wherein the second solvent comprises one or more of tetrahydrofuran, toluene, methanol or ethanol.

Embodiment 21. The method according to any of embodiments 12-20, wherein the second solvent is heated to a temperature of 30 ° C to the boiling point of the second solvent.

Embodiment 22. The method according to any of embodiments 12-21, wherein the first solvent and the second solvent are the same.

An implementation option 23. The method according to any of embodiments 12-22, where in stage (D) compound 1 is crystallized in the presence of seed crystals of polymorphic form B.

An implementation option 24. The method according to any of embodiments 12-22, where in stage (D) compound 1 is crystallized in the presence of a third solvent and seed crystals of polymorphic form B.

Embodiment 25. The method of Embodiment 24, wherein the third solvent comprises one or more of water, C ₁ -C ₄ alkanol, C ₅ -C ₈ hydrocarbon, or aromatic C ₇ -C ₉ hydrocarbon.

Embodiment 26. The method of Embodiment 25, wherein the third solvent comprises one or both of water or methanol.

Embodiment 27. A method for preparing a crystalline form of Compound 1 described in the Summary of the invention, comprising (A) contacting 1- (2-bromo-4-fluorophenyl) -2-propanone and 1-chloro-3-fluoro-2-isothiocyanatobenzene in the presence of a first solvent to form a reaction mixture containing a salt of the condensation product, (B) contacting the salts of the condensation product with an alkylating agent to form an alkylated thioamide intermediate, (C) optionally isolating an alkylated thioamide weft compound, (D) contacting the alkylated thioamide intermediate with methylhydrazine in the presence of a second solvent to form a reaction mixture containing compound 1 and (E) crystallizing the compound 1 as polymorphic Form B.

Embodiment 28. The method of Embodiment 27 wherein the alkylated thioamide intermediate is isolated in step (C).

Embodiment 29. The method of Embodiment 27 wherein the alkylated thioamide intermediate is not isolated in step (C).

Embodiment 30. The method of any of Embodiments 27-29 wherein the alkylated thioamide intermediate is 3- (2-bromo-4-fluorophenyl) -4 - [(2-chloro-6-fluorophenyl) amino] -4- ( methylthio) -3-buten-2-one.

Embodiment 31. A method according to any one of embodiments 27-30, wherein the solvent includes one or more of the complex C _4- C ₈ ether, C _1- C ₄ alkanol, C _3- C ₈ ketone, C _4- C ₈ ether, C ₂ -C ₇ nitrile or aromatic C _{7 -C 9} hydrocarbon.

Embodiment 32. The method of Embodiment 31, wherein the first solvent comprises one or more of tetrahydrofuran or methyl tert- butyl ether.

An implementation option 33. The method according to any of embodiments 27-32, where the first solvent is cooled to a temperature of from 0 ° C to 15 ° C.

Embodiment 34. A method according to any one of embodiments 27-33, wherein the second solvent comprises one or more of water, a complex C _4- C ₈ ether, C _1- C ₄ alkanol, C _3- C ₈ ketone, C _{4 -} C ₈ ether, C ₂ -C ₇ nitrile or aromatic C ₇ -C ₉ hydrocarbon.

Embodiment 35. The method of Embodiment 34, wherein the second solvent comprises one or more of tetrahydrofuran, toluene, methanol or ethanol.

Embodiment 36. The method according to any of embodiments 27-35, wherein the second solvent is heated to a temperature of 30 ° C. to the boiling point of the second solvent.

Embodiment 37. The method according to any of embodiments 27-36, wherein the first solvent and the second solvent are the same.

An implementation option 38. The method according to any of embodiments 27-37, where in stage (D) compound 1 is crystallized in the presence of seed crystals of polymorphic form B.

An implementation option 39. The method according to any of embodiments 27-37, where in stage (D) compound 1 is crystallized in the presence of a third solvent and seed crystals of polymorphic form B.

Embodiment 40. The method of Embodiment 39, wherein the third solvent comprises one or more of water, a C ₁ -C ₄ alkanol, a C ₅ -C ₈ hydrocarbon, or an aromatic C ₇ -C ₉ hydrocarbon.

Embodiment 41. The method of Embodiment 40, wherein the third solvent comprises one or both of water or methanol.

Embodiment 42. A composition for protecting a plant or plant seed from diseases caused by fungal pathogens, described in the Summary of the Invention, comprising (a) a polymorphic Form A of compound 1 and (b) at least one additional component selected from the group consisting of surface - active substances, solid diluents and liquid carriers.

Embodiment 43. The composition described in the summary of the invention for protecting a plant or plant seed from diseases caused by fungal pathogens, comprising (a) a polymorphic Form B of compound 1 ; and (b) at least one additional component selected from the group consisting of surfactants, solid diluents, and liquid carriers.

Embodiment 44. A composition for protecting a plant or plant seed from diseases caused by fungal pathogens described in a summary of the invention, comprising (a) a polymorphic Form A of compound 1 ; and (b) at least one other nematicide, insecticide and / or fungicide.

An implementation option 45. Described in the brief description of the invention, a composition for protecting a plant or plant seed from diseases caused by fungal pathogens, containing (a) a polymorphic form In compound 1 ; and (b) at least one other nematicide, insecticide and / or fungicide.

Embodiment 46. The method described in the summary of the invention for protecting a plant or seed from diseases caused by fungal pathogens, comprising applying to the plant or seed, or the environment in which the plant or seed is located, a biologically effective amount of compound 1 , including polymorphic form A.

Embodiment 47. The method described in the summary of the invention for protecting a plant or seed from diseases caused by fungal pathogens, comprising applying to the plant or seed, or the environment in which the plant or seed is located, a biologically effective amount of compound 1 , including polymorphic form B.

Embodiments of the present invention, including the above-described embodiments 1-47, as well as any other embodiments described herein, may be combined by any means.

Compound 1 is 4- (2-bromo-4-fluorophenyl) - N - (2-chloro-6-fluorophenyl) -1,3-dimethyl-1 H -pyrazole-5-amine and has the following molecular structure:

It was found that compound 1 in the solid state can be obtained in more than one solid form. These solid forms include an amorphous solid form in which there is no long range order in the positions of the molecules (e.g., foams and glass). These solid forms also include crystalline forms in which the constituent molecules are arranged according to an orderly repeating structure propagating in all three spatial dimensions. The expression “polymorph” refers to a particular crystalline form of a chemical compound that can exist in more than one crystalline structure (eg, lattice type) in the solid state. The term “packaging polymorphs” refers to specific crystalline forms of a compound characterized by different crystalline packaging. The crystalline forms of compound 1 in accordance with the present invention relate to embodiments that include one polymorph (i.e., one crystalline form) and to embodiments that include a mixture of polymorphs (i.e., various crystalline forms). Polymorphs can differ in such chemical, physical, and biological properties as crystal shape, density, hardness, color, chemical stability, melting point, hygroscopicity, suspendibility, solubility, dissolution rate, and bioavailability. One skilled in the art will understand that a polymorph of compound 1 can exhibit beneficial effects (e.g., suitability for preparing useful formulations, stability, improved biological effectiveness) compared to another polymorph or mixture of polymorphs of compound 1 . Differences in chemical stability, filterability, solubility, hygroscopicity, melting point, solid density and fluidity can have a significant impact on the development of production methods and compositions, as well as on the effectiveness of control of plant diseases. To date, the preparation and isolation of specific polymorphs of compound 1 has been carried out.

One crystalline polymorphic form of compound 1 is designated as polymorphic form A. This solid form is unsolvated. Polymorphic form A can be characterized using x-ray powder diffraction, x-ray diffraction analysis of single crystals and differential scanning calorimetry (DSC).

The X-ray powder diffraction pattern of the polymorphic form A of compound 1 is shown in Figure 1A. The corresponding 2θ values are presented in tabular form in table 2 of the characterization example 1. The polymorphic form A of compound 1 can be identified using a powder X-ray diffraction pattern in Cu (Kα1) at room temperature having at least the following reflection positions at 2θ angles (in degrees) :

2θ 2θ 6,395 22.23 12,668 23,885 14,507 24,919 14,99 26.34 18,984

X-ray diffraction of single crystals can also be used to determine the characteristics of polymorphic form A. A description of the X-ray diffraction of single crystals of polymorphic form A is presented in the example of determining characteristics 3. Crystals of polymorphic form A have a monoclinic unit cell, and among them there can be many morphological types, the most typical being disordered lamellar morphological type.

The polymorphic form A of compound 1 can also be characterized using differential scanning calorimetry (DSC). DSC indicates that the melting point of polymorphic form A is approximately 168 ° C. Details of the DSC experiment are presented in the characterization example 9. Polymorphic form A in its pure solid form is physically and chemically stable.

Pure polymorphic form A can be obtained in a direct manner during the preparation of compound 1 , as described in Production Examples 1 and 2.

Another crystalline polymorphic form of compound 1 is designated as polymorphic form B. This solid form is unsolvated. Polymorphic form B can be characterized using x-ray powder diffraction, x-ray diffraction analysis of single crystals and differential scanning calorimetry.

The X-ray powder diffraction pattern of the polymorphic form B of compound 1 is shown in Figure 1B. The corresponding 2θ values are presented in tabular form in table 3 of the characterization example 2. The polymorphic form B of compound 1 can be identified using a powder X-ray diffraction pattern in Cu (Kα1) at room temperature having at least the following reflection positions at 2θ angles (in degrees) :

2θ 2θ 10,894 24,285 15,361 25.84 16,134 27.54 17,718 29,449 20,322

X-ray diffraction of single crystals can be used to determine the characteristics of polymorphic form B. A description of the X-ray diffraction of single crystals of polymorphic form B is presented in the example of determining characteristics 4. Crystals of polymorphic form B have an orthorhombic unit cell, and among them there can be many morphological types, with the most typical prismatic morphological type.

The polymorphic form B of compound 1 can also be characterized by differential scanning calorimetry. DSC indicates that the melting point of polymorphic form B is approximately 143 ° C. Details of the DSC experiment are presented in Characterization Example 9.

Polymorphic form B can be obtained directly by the method as described in Production Examples 4 and 5. Polymorphic form B can also be obtained from isolated polymorphic form A or mixtures of forms A and B by suspension of the polymorphs in a solvent with optional heating and then cooling back to room temperature temperatures or lower, as described in Production Examples 3, 6, 7, and 8.

Compound 1 may also exist as an amorphous solid. The powder x-ray diffraction pattern (pXRD) for the amorphous form of compound 1 shows a picture with a wide range of reflection in the two-theta angle, which does not have distinct reflection signals and, thus, is easily distinguishable from x-ray diffraction patterns of crystalline forms of compound 1 . An amorphous solid form can be obtained using standard methods known in the art, such as evaporating to dryness solutions of compound 1 , rapidly cooling the molten compound 1 , spray drying a solution of compound 1, or freeze-drying a frozen solution containing compound 1 .

The preparation of the polymorphic form A of compound 1 can be carried out using a process where compound 1 is prepared from its starting materials, as described in Production Examples 1 and 2. Production Examples 1 and 2 are slightly different processes for preparing the starting materials 1- (2-bromo-4 -fluorophenyl) -2-propanone (compounds of formula 2 ) and 1-chloro-3-fluoro-2-isothiocyanatobenzene (compounds of formula 3 ). Production Examples 1 and 2 also represent a slightly different treatment of the salt of the starting condensation product (compound of formula 4 ), which is either oxidized to form a thioamide intermediate (compound of formula 5 ) or alkylated to form an alkylated thioamide intermediate (compound of formula 5a ). Any intermediate can react with methylhydrazine to produce a compound of formula 1 (4- (2-bromo-4-fluorophenyl) - N - (2-chloro-6-fluorophenyl) -1,3-dimethyl-1 H -pyrazole-5- amine compound 1 ).

A particularly applicable method for preparing compound 1 is shown in Scheme 1 and is presented as an example in Production Examples 1 and 2. The method comprises treating a compound of formula 2 with a base in a solvent and then additionally contacting a compound of formula 3 to form a salt of the starting condensation product (compound of formula 4 ) . A salt of formula 4 can be neutralized with an acid to form a thioamide intermediate of formula 5, or it can be alkylated to form an alkylated thioamide intermediate of formula 5a . Intermediates of formula 5 or 5a are optionally isolated or in situ reacted with methyl hydrazine in the presence of a solvent for the compound of formula 1 .

The starting ketone of formula 2 can be obtained in accordance with several methods. One production method begins with 2-bromo-4-fluorobenzeneacetonitrile, as described in world patent publication WO 2012/031061 (Synthesis Example 7, Step A). A ketone of formula 2 can also be prepared starting with 2-bromo-4-fluorobenzeneacetic acid, as described in Production Example 1, Step A, and 2-bromo-4-fluoroaniline, as described in Production Example 2, Step A, of this description. The starting isothiocyanate of formula 3 can be obtained from 2-chloro-6-fluorobenzeneamine (also called 2-chloro-6-fluoroaniline) using thiophosgene as described in Production Example 1, Step B. The starting isocyanate of Formula 3 can also be obtained using a multistep process. as described in Production Example 2, Step B.

Scheme 1

The first step of Scheme 1 involves the condensation of a ketone of formula 2 with an isothiocyanate of formula 3 , in the presence of a base to form a salt of the starting condensation product (compound of formula 4 ). Bases suitable for the condensation reaction include hydrides, alkoxides, hydroxides or carbonates of sodium or potassium, such as sodium hydride, potassium t -butoxide, sodium ethoxide, potassium hydroxide, sodium hydroxide or potassium carbonate. Amine bases (e.g. triethylamine or N , N- diisopropylethylamine) can also be used to effect condensation. A particularly suitable base is sodium hydroxide.

A number of solvents are suitable for condensation and can be a C ₄ -C ₈ ester, C ₁ -C ₄ alkanol, C ₃ -C ₈ ketone, C ₄ -C ₈ ether, C ₂ -C ₇ nitrile or aromatic C ₇ -C ₉ hydrocarbon or mixtures thereof. Suitable solvents include tetrahydrofuran, methyl tert- butyl ether, toluene, tert- butanol, ethanol, ethyl acetate, or mixtures thereof. Particularly suitable solvents are tetrahydrofuran and methyl tert- butyl ether. Solvents are usually selected in terms of compatibility with the base selected for the reaction. The solvent used for the condensation step is referred to as the first solvent. Phase transfer catalysts can also be used if the base has limited solubility in a solvent. For example, in Production Example 2, Step C, tetrabutylammonium bromide is added to a mixture of potassium hydroxide in tetrahydrofuran. Tetrabutylammonium hydroxide is formed and acts as a soluble form of the hydroxide base in an ether solvent. It is also important to minimize the amount of water in the reaction, since water can lead to hydrolysis of the compound of formula 3 .

Condensation can be performed at a temperature ranging from below about -78 ° C to a higher boiling point of the solvent. A particularly suitable temperature range is from -10 ° C to 20 ° C. Condensation can be accomplished by adding a mixture of compounds of formulas 2 and 3 to a cooled solution of a base in a solvent, or more preferably first adding a ketone of formula 2 to a cooled solution of a base in a solvent and reacting it with a base for a period of time (1 hour or less) and then adding an isothiocyanate of the formula 3 . The ratio of base to compound of formula 2 is usually in the range from 1.0: 1.0 to 1.5: 1.0 with a slight preferred excess in the range from 1.1: 1.0 to 1.3: 1.0, depending from solubility and reactivity of the base. The molar ratio of the compound of formula 3 to the compound of formula 2 can vary from 0.9: 1.0 to 1.2: 1.0. A particularly suitable range of the molar ratio of the compound of formula 3 to the compound of formula 2 is from 0.95: 1.00 to 1.10: 1.00.

The starting product of condensation is a salt of a thioamide intermediate compound (compounds of formula 4 ). The salt of the condensation product of formula 4 is generally not isolated, but is instead treated in situ with acid to form a thioamide intermediate of formula 5 or treated with an alkylating agent to form an alkylated thioamide intermediate of formula 5a . A number of acids are suitable for neutralizing a salt of formula 4 , such as acetic acid, hydrochloric acid or citric acid. The required amount of acid is one that will give a neutral or very slightly acidic pH. Acetic acid or citric acid is particularly suitable for thoroughly neutralizing the reaction mixture to a neutral pH. The reaction mixture containing a thioamide intermediate is treated with water and worked up in the usual way to isolate α-acetyl-2-bromo- N - (2-chloro-6-fluorophenyl) -4-fluorobenzene-ethanethioamide (compounds of formula 5 ) as a solid (described in Production Example 2, Step C). A number of alkylating agents can be used to convert a salt of formula 4 to an alkylated thioamide intermediate of formula 5a , where R is lower alkyl (e.g. methyl, ethyl or n- propyl). Compounds such as iodomethane, iodoethane, 1-bromopropane or dimethyl sulfate are suitable alkylating agents. A typical ratio of alkylating agent to compound of formula 2 is from 1.1: 1.0 to 1.3: 1.0. The reaction mixture containing the alkylated thioamide intermediate of formula 5a is treated with aqueous acid and processed in the usual way to isolate the intermediate as a solid. For example, when using iodomethane as an alkylating agent, 3- (2-bromo-4-fluorophenyl) -4 - [(2-chloro-6-fluorophenyl) amino] -4- (methylthio) -3-buten-2-one is isolated (compound of formula 5a , where R = methyl) (described in Production Example 1, Step C).

The second step of Scheme 1 involves the reaction of intermediates of formulas 5 or 5a with methyl hydrazine. Intermediates can be isolated and purified prior to reaction with methyl hydrazine in a solution, which may be different from that for the first step of Scheme 1. Alternatively, intermediates can be immediately reacted in situ with methyl hydrazine in the starting reaction mixture. An example of a methylated thioamide intermediate (Formula 5a where R = methyl) is reacted with methylhydrazine without prior isolation, can be found in International Patent Application Publication WO 2012/031061 (Synthesis Example 7, Step C). An example of a methylated thioamide intermediate (formula 5a , where R = methyl) reacting with methyl hydrazine after the initial isolation is described in Production Example 1, Step D. An example of a thioamide intermediate (formula 5 ) reacting with methyl hydrazine after the initial isolation is described in the Production Example 2, stage D.

The formation of a pyrazole ring in the second step of Scheme 1 requires a reaction between a thioamide intermediate (or an alkylated thioamide intermediate) and a buffered solution of methylhydrazine. The pH of the reaction medium affects the ratio of regioisomeric pyrazoles, which can be obtained from the reaction of methylhydrazine and the ketothioamide functional group of intermediate 5 or 5a . The regioisomeric products of this reaction are 4- (2-bromo-4-fluorophenyl) - N - (2-chloro-6-fluorophenyl) -1,3-dimethyl-1 H -pyrazole-5-amine (compound of formula 1) and 4 - (2-bromo-4-fluorophenyl) - N - (2-chloro-6-fluorophenyl) -1,5-dimethyl-1 H -pyrazol-3-amine. It was found that to ensure the maximum ratio (approximately 16: 1 towards the compound of formula 1 ) of the pyrazole isomers, the optimum pH is from 4 to 5. If the pH is too low, the reaction proceeds very slowly, and if the pH is too high, then the regioselectivity is negligible . The pH range can be obtained using a number of buffer systems. The methylhydrazine free base can be combined with more than one equivalent of acetic acid to give a suitably buffered solution. The amount of acetic acid may range from 1.1 to 2.5 equivalents, with a preferred ratio of free methylhydrazine to acetic acid of 1.0: 2.0. Alternatively, methylhydrazine sulfate can be used as a source of methylhydrazine and treated with more than one equivalent of triethylamine or sodium acetate. The amount of base (triethylamine or sodium acetate) may range from 1.1 to 2.5 equivalents. The molar ratio of methylhydrazine to thioamide intermediate 5 or 5a is usually in the range of 1.1: 1.0 to 5.0: 1.0. Particularly suitable ratios of methylhydrazine to thioamide intermediate are in the range of 1.2: 1.0 to 2.5: 1.0.

A number of solvents are suitable for forming a pyrazole ring and may be water, a C ₄ -C ₈ ester, a C ₁ -C ₄ alkanol, a C ₃ -C ₈ ketone, a C ₄ -C ₈ ether, a C ₂ -C ₇ nitrile, or aromatic C _7- With ₉ hydrocarbon or mixtures thereof. Solvents are usually selected for their compatibility with the intermediate of formula 5 or 5a and the methyl hydrazine reagent. The buffered solution of methyl hydrazine usually needs to be polar in order to dissolve or partially dissolve the salts that make up the buffered solution. Solvents like methanol, ethanol or tetrahydrofuran / water mixtures are particularly suitable for a solution of methylhydrizine. An intermediate of formula 5 or 5a may be dissolved in the same solvent as methylhydrazine, or it may be in a different solvent. Particularly suitable solvents for dissolving the thioamide intermediate are tetrahydrofuran, toluene and ethanol. The solvent can affect the regioselectivity of the reaction and the mixture of solvents (a solution of methylhydrazine in methanol and a thioamide intermediate in toluene) has been found to provide a high level of regioselectivity. The solvent or solvents used to form the pyrazole ring are referred to as the second solvent. An intermediate of formula 5 or 5a can be added to a methyl hydrazine solution or a methyl hydrazine solution can be added to a thioamide intermediate. The order of addition leads to the formation of the preferred pyrazole in sufficient quantity. The order of addition is generally determined by whether or not a thioamide intermediate is secreted.

Obtaining pyrazole can be performed at a temperature in the range from about 20 ° C to the boiling point of the solvent. A particularly suitable temperature range is from 40 ° C to 75 ° C. The reaction is usually monitored by high pressure liquid chromatography to determine the duration of heating. The time required to complete the reaction, to a certain extent, depends on the scale of the reaction. A typical period of time necessary to maximize the production of pyrazole (formation of a compound of formula 1 ) is in the range from 3 to 18 hours.

Upon completion of the reaction, the reaction mixture is usually diluted with aqueous solutions to dissolve salts (triethylamine sulfate, sodium acetate) and reduce the solubility of the product, thus promoting crystallization of the product with high purity. The reaction mixture can be treated with various aqueous solutions, for example, aqueous sodium or potassium carbonate, aqueous hydrochloric acid, or neutral water. Another option is to replace the reaction solvent with another, as described in Production Example 2, Step D. Solvent replacement is sometimes preferred to replace the solvent with some water solubility or high boiling point with a solvent with very low water solubility and / or lower boiling point for facilitate the dissolution of salts in the aqueous phase and the removal of solvent from the product. The organic phase containing compound 1 , which is formed as a result of water washings and optional solvent exchange, can be processed in accordance with two different methods.

The first treatment option for the organic phase containing compound 1 includes a solvent concentration of up to about 20-40% of its original volume. This reduces the amount of extraction solvent in which compound 1 is dissolved (i.e., toluene). The resulting suspension of compound 1 is treated with seed crystals of polymorphic form B and optionally heated to 25-60 ° C to facilitate crystallization into the preferred polymorphic form B and the conversion of any form A to form B. Crystallization time is determined by analysis of aliquots of the suspension sample using X-ray powder diffraction. When the crystallization of polymorphic form B is complete, the suspension is diluted with another solvent (for example, heptane) in which compound 1 is less soluble to facilitate filtration and recovery of polymorphic form B of compound 1 . This direct conversion method, without first isolating the solid polymorphic form A, is described in Production Example 4. Alternatively, a solvent containing a suspension of compound 1 can be replaced for the crystallization method. The starting solvent for extraction can be minimized and replaced with a third solvent to facilitate crystallization of polymorphic form B. A number of solvents are suitable for the crystallization process and can be water, C ₄ -C ₈ ester, C ₁ -C ₄ alkanol, C ₃ -C ₈ ketone, C ₄ -C ₈ ether, C ₂ -C ₇ nitrile or aromatic C ₇ -C ₉ hydrocarbon or mixtures thereof. The solvent used for the crystallization process is referred to as a third solvent. The suspension in the third solvent is treated with seed crystals of polymorphic form B, optionally heated to 25-60 ° C and controlled by x-ray powder diffraction analysis. When the crystallization of polymorphic Form B is complete, the suspension is diluted with another solvent (e.g., water) in which Compound 1 is less soluble to facilitate filtration and recovery of the polymorphic Form B of Compound 1 . This alternative direct conversion method, without prior isolation of the solid polymorphic form A, is described in Production Example 5.

A second treatment option for the organic phase containing compound 1 involves cooling the organic phase to a temperature in the range of 5 to 25 ° C. and filtering the product which precipitates. A wet solid can be washed with water to remove traces of salts and washed with an organic solvent, such as hexane or heptane, to displace water and solvents boiling at high temperatures (e.g. toluene) to facilitate drying. The separated solid or wet cake of compound 1 can then be further isolated by drying or removing the last traces of solvent remaining on the external surface of the solid in a vacuum oven. The isolated solid can be characterized using a number of analytical methods. Obtaining compound 1 in accordance with this method, as a rule, leads to the formation of polymorphic form A (as described in examples of obtaining 1 and 2) or a mixture of polymorphic form A and form B, where form A predominates. In order to obtain a pure sample of polymorphic form B, the isolated solid product obtained by methods such as Production Example 1 or 2 is subjected to a polymorph conversion process as described in Production Examples 3 and 6-8.

A number of methods can be used to obtain the polymorphic form B of compound 1 . The choice of optimal methods, as a rule, is based on a number of factors, including the scale of the reaction. The temperature range for conversion can vary from 20 ° to the boiling point of the solvent. Performing the conversion at temperatures in the range of 20-30 ° C provides mild conditions. The time required for conversion can vary depending on the scale of the reaction and the solvent, but, as a rule, can be completed from 1 to 18 hours. A number of solvents can be used for the conversion process. Suitable solvents include water, C ₄ -C ₈ ester, C ₁ -C ₄ alkanol, C ₃ -C ₈ ketone, C ₄ -C ₈ ether, C ₂ -C ₇ nitrile or aromatic C ₇ -C ₉ hydrocarbon, or mixtures. Particularly suitable solvents include water, butyl acetate, methanol, 1-propanol or toluene. A mixture of methanol and water at ambient temperature is particularly suitable as described in Production Examples 3 and 5.

Seed crystals are generally useful in processes for transforming polymorphic forms. Seed crystals are used to provide conversion and / or increase the rate of conversion of polymorphic form A to polymorphic form B. Mixtures in which polymorph conversion reactions occur are often mixed using a number of methods, even if not explicitly indicated. The form of mixing may be shaking the reaction vessel or shaking with a magnetic or mechanical stirrer. Mixtures in which polymorph conversion reactions occur can also be mixed using a solvent boiling process. Effective mixing is not necessary for the conversion of polymorphic forms, but mixing can increase the efficiency of the method and reduce the reaction time.

Polymorphic form B was first discovered as described in Production Example 9. It was isolated from an unstable composition, where polymorphic form A spontaneously turned into polymorphic form B. It was the source of seed crystals for some transformation experiments.

The relative stability of the polymorphic forms A and B of compound 1 was studied. Two polymorphic forms were subjected to experiments on the study of competitive mutual transformations. Examples of characterization 6, 7 and 8 demonstrate that polymorphic form B is a more thermodynamically stable form at temperatures used in the studies (20-50 ° C). Characterization Example 5 describes the heating of a sample of polymorphic form B and the control of its powder X-ray diffraction pattern. Analysis of the experiment indicates that the polymorphic form B of compound 1 continues to exist heated from room temperature to approximately 138 ° C when it turns into polymorphic form A. The newly formed polymorphic form A continues to exist until it melts at approximately 160 °. The presence of the conversion of a solid into a solid, below the melting point, upon heating of polymorphic form B indicates an enantiotropic bond between polymorphic forms A and B, i.e. polymorphic form B is more stable below the transition temperature, and polymorphic form A is more stable above the transition temperature. Characterization Example 9 describes differential scanning calorimetry experiments for polymorphic forms A and B. An analysis of the experiment shows an endothermic transition of polymorphic form B to form A, indicating an enantiotropic relationship between the two forms, i.e. polymorphic form B is more stable below the transition temperature (approximately 148 ° C), and polymorphic form A is thermodynamically more stable above the transition temperature. Differences in the transition temperature between the two experiments can be observed due to the heating rate and other studied parameters. Examples of characterization 3 and 4 are calculated densities of two crystalline forms based on x-ray data of single crystals. The density of polymorphic form B (1.673 g / cm ³ ) is higher than the density of polymorphic form A (1.604 g / cm ³ ), which is consistent with the density rule, which determines that the most stable polymorph will have the highest density (R. Hilfiker (ed. ), “Polymorphism in the Pharmaceutical Industry”, 2006, page 33, Wiley-VCH, Weinheim, Germany).

Without further elaboration, it is believed that one skilled in the art may, using the preceding description, use the present invention. The following examples, therefore, are regarded as merely illustrative and in no way limiting the present disclosure. The source material for the following examples does not have to be obtained in the course of a specific production process, the procedure of which is described in other examples. The analytical methods used in the preparation examples are described below or in the characterization examples.

Proton Nuclear Magnetic Resonance ( ¹ H-NMR)

Proton NMR analysis was performed on a Bruker Advance 300/400 device. The operating frequency was 400 MHz, the spectral frequency range was 0-16 ppm (particles per million), the exposure time was 2 seconds, the pulse duration was 12 μs, the minimum number of scans was 8. Samples were obtained by weighing approximately 0.01 g of samples or reference standards, adding 0.6 ml of DMSO-d6 to dissolve the contents and transfer to NMR tubes. Deuterated DMSO (DMSO-d6) was obtained from Cambridge Isotope Laboratory. Spectrum ¹ H-NMR is recorded in ppm with a shift in the direction of the weak field from tetramethylsilane; “S” means singlet, “d” means doublet, “t” means triplet, “m” means multiplet, “dd” means double doublet, and “br s” means wide singlet.

PRODUCTION EXAMPLE 1

Synthesis of polymorphic form A of compound 1 (form A)

Stage A: Obtaining 1- (2-bromo-4-fluorophenyl) -2-propanone

Acetic anhydride (950 ml, 10 mol) was degassed by bubbling nitrogen through it at room temperature. 2-bromo-4-fluorobenzeneacetic acid (233 g, 1.0 mol) was dissolved in acetic anhydride, cooled in an ice bath and treated dropwise with methylimidazole (80 ml, 1.0 mol). The mixture was warmed to room temperature for 18 hours. The reaction mixture was concentrated in vacuo, the resulting brown oil was added to a shaken ice-water mixture (500 ml) and allowed to warm to room temperature over 18 hours. Diethyl ether (400 ml) was added and the mixture was separated. The aqueous phase was extracted with diethyl ether and the combined organic phases were washed with water, saturated aqueous sodium bicarbonate and 1N. hydrochloric acid. The ether solution was dried (MgSO ₄ ), filtered and concentrated in vacuo to give a dark amber oil (228 g). The crude oil was dissolved in methanol (600 ml), treated dropwise with 1 N. aqueous sodium hydroxide solution (200 ml) and shaken at room temperature for 18 hours. The reaction mixture was concentrated in vacuo to remove most of the methanol, diluted with ice and treated with aqueous hydrochloric acid to acidify the mixture. The aqueous mixture was extracted with diethyl ether, and the combined organic phases were dried (MgSO ₄ ), filtered and concentrated in vacuo to give a dark amber oil (215 g). The crude oil was further purified by distillation under reduced pressure (6-7 mm Hg), heating from 115 to 120 ° C to form the title product as a clear yellow oil (171 g).

^{1 H} NMR (CDCl ₃ ) δ 7.34-7.32 (dd, 1H), 7.20-7.17 (dd, 1H), 7.03-7.00 (td, 1H), 3.84 ( s, 2H); 2.23 (s, 3H).

Stage B: Obtaining 1-chloro-3-fluoro-2-isothiocyanatobenzene

A solution of 2-chloro-6-fluorobenzeneamine (29.2 g, 0.20 mol) in chlorobenzene (200 ml) was treated with N, N-dimethylformamide (0.10 ml) and then thiophosgene (27.6 g, 0.24 mol ) dropwise at room temperature. The reaction mixture was refluxed for 2.5 hours and shaken at room temperature for 18 hours. The suspension was filtered through a pad of silica gel and washed with hexane. The filtrate was concentrated in vacuo to give a crude oil, which was chromatographed on silica gel with hexane to give the title compound as a pale yellow oil (31.5 g).

¹ H NMR (CDCl ₃ ) δ 7.23-7.19 (m, 1H), 7.18-7.13 (td, 1H), 7.10-7.04 (m, 1H).

Step C: Preparation of 3- (2-bromo-4-fluorophenyl) -4 - [(2-chloro-6-fluorophenyl) amino] -4- (methylthio) -3-buten-2-one

To a solution of potassium tert -butoxide (23.5 g, 0.21 mol) in methyl tert- butyl ether (350 ml) was added a solution of 1- (2-bromo-4-fluorophenyl) -2-propanone ( i.e. the product of step A) (44.0 g, 0.19 mol) in methyl tert- butyl ether (70 ml) dropwise over 15 minutes at 10 ° C. The mixture was stirred for 1 hour at 5-10 ° C. and then treated with a solution of 1-chloro-3-fluoro-2-isothiocyanatobenzene (i.e., the product of step B) (32.0 g, 0.17 mol) in methyl- tert- butyl ether (40 ml). The reaction mixture was agitated at 10 ° C. for 15 minutes and then the mixture was heated. After 30 minutes, when the temperature was 17 ° C, the suspension was treated with methyl iodide (15 ml, 0.24 mol) in methyl tert- butyl ether (15 ml) and continued to warm to room temperature for 2 hours. The resulting suspension was poured into a mixture of 1 N. hydrochloric acid (250 ml) and ice (200 g) were separated and the aqueous phase was extracted with methyl tert- butyl ether. The combined organic phases were washed with saturated aqueous NaCl, dried (MgSO ₄ ), filtered and concentrated in vacuo to give a solid, which was suspended in cold methanol (100 ml). The suspension was filtered, the filter cake was rinsed with cold methanol (10 ° C) and dried under vacuum to form the title compound as an almost white solid (63.2 g).

¹ H NMR (CDCl ₃ ) δ 12.75 (s, 1H), 7.43-7.41 (dd, 1H), 7.34-7.32 (dd, 1H), 7.28-7.16 (m, 2H), 7.10-7.05 (m, 2H), 1.92 (s, 3H), 1.86 (s, 3H).

Stage D: Obtaining 4- (2-bromo-4-fluorophenyl) - N - (2-chloro-6-fluorophenyl) -1,3-dimethyl-1 H pyrazole-5-amine

A solution of concentrated sulfuric acid (16 ml, 0.30 mol) in ethanol (500 ml) was treated with methylhydrazine (15 ml, 0.29 mol) in ethanol (50 ml) dropwise at room temperature. The reaction mixture was heated to give a white suspension. Triethylamine (63 ml, 0.45 mol) in ethanol (50 ml) was added dropwise, while the mixture was at 30-35 ° C. The solids were dissolved and the solution was treated with 3- (2-bromo-4-fluorophenyl) -4 - [(2-chloro-6-fluorophenyl) amino] -4- (methylthio) -3-buten-2-one (i.e. the product of step C) (63.2 g, 0.145 mol) and heated to 75 ° C for 18 hours. The reaction mixture was cooled to 25-28 ° C and treated with 1 N. sodium hydroxide solution (600 ml). The resulting suspension was cooled to 15 ° C and treated with water (300 ml). The suspension was filtered, the solids were washed with water and dried under vacuum to form the title compound as a white solid (54.5 g). The melting temperature determined on the EZ-Melt apparatus (optical melting temperature of a standard research system) was 167.5-168.1 ° C.

¹ H NMR (CDCl ₃ ) δ 7.25-7.23 (dd, 1H), 7.06-7.03 (dd, 1H), 6.96-6.94 (dt, 1H), 6.89 -6.85 (td, 1H), 6.79-6.75 (m, 1H), 6.70-6.66 (m, 1H), 5.46-5.43 (br.d, 1H) 3.80 (s, 3H); 2.10 (s, 3H).

PRODUCTION EXAMPLE 2

Synthesis of polymorphic form A of compound 1 (form A)

Stage A: Obtaining 1- (2-bromo-4-fluorophenyl) -2-propanone

Water (1 L) was treated with concentrated sulfuric acid (202 g, 98%) for 30 minutes and then the aqueous acid solution was cooled to 2 ° C. 2-bromo-4-fluoroaniline (190 g, 1.0 mol) was added over 5 minutes and the solution was further cooled to 0 ° C. A solution of sodium nitrite (72.5 g, 1.05 mol) in water (110 ml) was added over 60 minutes, while the internal temperature was kept below 5 ° C. The resulting suspension of the diazonium salt was treated with isopropenyl acetate (220 g, 2.2 mol), then copper sulfate pentahydrate (12.4 g, 0.05 mol) and shaken for 30 minutes, during which the copper sulfate dissolves. A solution of sodium sulfite (24 g, 0.2 mol) in water (80 ml) was added dropwise over 3 hours, while maintaining the temperature from 10 to 20 ° C. After stirring the mixture for an additional 30 minutes at 20 ° C., hexanes (1 L) were added and the mixture was separated. The aqueous phase was extracted with hexanes (2 × 500 ml). The combined organic phases were washed with aqueous sodium hydroxide (0.5N, 500 ml) and water (500 ml) and concentrated under reduced pressure to a brown oil (200 g).

The crude product could be purified by distillation under reduced pressure, as in Production Example 1, or it could be purified using a bisulfite adduct, as described below.

The crude 1- (2-bromo-4-fluorophenyl) -2-propanone (26.2 g, 0.11 mol) in heptane (104 ml) was treated with a solution of sodium metabisulfite (30 g, 0.16 mol) in water (52 ml). The mixture was shaken at 25 ° C for 12 hours. The suspension was filtered, the filter cake was washed with heptane (50 ml) and dried under vacuum for 1 hour to form a bisulfite adduct as a pale yellow solid (39 g). The bisulfite adduct was treated with aqueous sodium hydroxide (10%, 104 ml) at 60 ° C for 1 hour. The mixture was cooled to 25 ° C and extracted with hexanes (2 × 100 ml). The combined organic phases were washed with water (20 ml) and concentrated under reduced pressure to give the title product (19.2 g) as a pale yellow oil.

¹ H NMR (CDCl ₃ ) δ 7.34-7.32 (dd, 1H), 7.20-7.17 (dd, 1H), 7.03-7.00 (td, 1H), 3.84 (s, 2H); 2.23 (s, 3H).

Stage B: Obtaining 1-chloro-3-fluoro-2-isothiocyanatobenzene

A mixture of ammonium thiocyanate (38 g, 0.50 mol) and anhydrous acetone (200 ml) was heated to 45 ° C. Benzoyl chloride (64 g, 0.46 mol) was added over 1 hour, while maintaining the temperature at 45-50 ° C. The mixture was heated for an additional hour at 45-50 ° C and then cooled to ambient temperature. The suspension was filtered and the solids were rinsed with anhydrous acetone (2 × 20 ml). The solids are removed and the benzoylisothiocyanate solution is used immediately.

A solution of 2-chloro-6-fluoroaniline (50.0 g, 0.345 mol) in anhydrous acetone (80 ml) was cooled to 5 ° C and treated with a solution of benzoylisothiocyanate at 5-10 ° C for 1 hour. The mixture was heated to 25-30 ° C for 2 hours. Water (500 ml) was added over 1 hour with thorough agitation and the mixture was agitated for an additional hour at ambient temperature. The mixture was filtered and washed with water (2 × 100 ml) and the resulting N - [[(2-chloro-6-fluorophenyl) amino] thioxomethyl] benzamide was dried in vacuo to give a solid (96 g).

¹ H NMR (CDCl ₃ ) δ 11.95 (s, 1H), 9.37 (s, 1H), 7.93 (m, 2H), 7.70 (m, 1H), 7.59 (m, 2H), 7.38 (m, 2H), 7.16 (m, 1H).

N - [[(2-chloro-6-fluorophenyl) amino] thioxomethyl] benzamide (96 g, 0.31 mol) was treated with an aqueous solution of sodium hydroxide obtained from water (190 ml) and concentrated sodium hydroxide (32 g 50%, 0.40 mol), and was heated at 73-78 ° C for 3 hours. The mixture was cooled to 10 ° C and treated with concentrated hydrochloric acid (6 g 36%, 0.06 mol) to a pH of about 7-9. After shaking for 30 minutes, the suspension was filtered and the filter cake was washed with cold (5 ° C) water (2 × 100 ml) and dried in a vacuum oven at 70 ° C to form a solid product (60 g) N - (2-chlorine) -6-fluorophenyl) thiourea.

¹ H NMR (DMSO-d6) δ 7.64 (s, 1H), 7.36 (m, 2H), 7.19 (m, 1H), 6.13 (s, 2H).

N - (2-chloro-6-fluorophenyl) urea (50.0 g, 0.245 mol) was dissolved in chlorobenzene (1.3 L) and the solution was heated to 60 ° C in vacuo to distill off approximately 20 ml of solvent to dry the reaction mixture. The vacuum was released and the mixture was quickly heated (heated under reflux for 1 hour) to 125-135 ° C with a slow subsurface bubbling of nitrogen to remove the released ammonium. The reaction was monitored by HPLC and, after completion, the mixture was cooled to ambient temperature and the solvent was distilled off under reduced pressure (10 mm Hg). When almost all chlorobenzene was removed, the mixture was diluted with cyclohexane (150 ml) and filtered to remove a small amount of insoluble material. The filtrate was concentrated to a crude liquid title product (1-chloro-3-fluoro-2-isothiocyanatobenzene) (40 g) and stored under nitrogen.

¹ H NMR (CDCl ₃ ) δ 7.23-7.19 (m, 1H), 7.18-7.13 (td, 1H), 7.10-7.04 (m, 1H).

Stage C: Obtaining α-acetyl-2-bromo- N - (2-chloro-6-fluorophenyl) -4-fluorobenzeneethanethioamide

A solution of potassium hydroxide (80 g 86%, 1.23 mol) and tetrabutylammonium bromide (9.0 g, 0.028 mol) in tetrahydrofuran (1.38 L) was cooled to 10 ° C under nitrogen. A solution of 1- (2-bromo-4-fluorophenyl) -2-propanone (i.e., the product of step A) (230 g, 0.944 mol) in tetrahydrofuran (460 ml) was added over 1 hour at 10-15 ° C. Then a solution of 1-chloro-3-fluoro-2-isothiocyanatobenzene (i.e., the product of stage B) (201 g, 1.04 mol) in tetrahydrofuran (460 ml) was added over 1 hour and the mixture was shaken at 10-15 ° C for 3 hours. The reaction mixture was further cooled to 0 ° C and treated with acetic acid (100 g, 1.67 mol) for 30 minutes to bring the reaction mixture to approximately pH 7. Water (1.15 L) and toluene (1.4 L) were added. and the phases were separated. The organic phase was washed with saturated aqueous sodium chloride (20 ml) and concentrated to a volume of approximately 250 ml under reduced pressure. The resulting suspension was treated dropwise with hexanes (1.15 L) to crystallize the product. The suspension was cooled to 5-10 ° C., filtered and the collected solids were washed with hexanes (400 ml). The solid title product (350 g) was dried in a vacuum oven. Melting point 138-142 ° C

¹ H NMR (CDCl ₃ ) δ 15.30 (s, 1H), 7.56 (m, 1H), 7.46 (m, 1H), 7.28 (m, 1H), 7.22 (m, 1H), 7.11 (m, 1H), 6.95 (m, 1H), 1.84 (s, 3H).

Stage D. Obtaining 4- (2-bromo-4-fluorophenyl) - N - (2-chloro-6-fluorophenyl) -1,3-dimethyl-1 H pyrazole-5-amine

A solution of sodium acetate (41 g, 0.50 mol) in methanol (200 ml) was treated with methylhydrazine sulfate (36 g, 0.25 mol) at 25 ° C under nitrogen atmosphere. The mixture was heated to 60 ° C for 30 minutes, during which time a liquid suspension formed. The mixture was cooled to ambient temperature, filtered, and insoluble solids were washed with methanol (50 ml). The filtrate was used as follows.

A solution of α-acetyl-2-bromo- N - (2-chloro-6-fluorophenyl) -4-fluorobenzene-ethanethioamide (i.e. the product of step C) (63 g, 0.15 mol) in toluene (300 ml) heated to 60 ° C and treated with a solution of methylhydrazine acetate. Hydrogen sulfide was formed during the addition and was oxidized in a scrubber filled with a disinfectant solution. The mixture was heated for 12 hours and then cooled to ambient temperature. Water (1 L) was added and the phases were separated. The aqueous phase was extracted with toluene and the combined organic phases were washed with hydrochloric acid (100 ml 1N) and water (100 ml). The combined organic phases were concentrated under reduced pressure and the concentrated solution was diluted with heptane (300 ml) and cooled to 5 ° C. The resulting suspension was filtered and the solid was dried under vacuum to give the title product (51 g). The melting point is 167-169 ° C ¹ H NMR (CDCl ₃ ) δ 7.25 (m, 1H), 7.10 (m, 1H), 7.00 (m, 1H), 6.90 (m, 1H ), 6.80 (m, 2H), 5.55 (br s, 1H), 3.89 (s, 3H), 2.17 (s, 3H).

PRODUCTION EXAMPLE 3

The conversion of polymorphic form A into form B of compound 1 using water and methanol

The polymorphic Form A of compound 1 (100 g, 0.242 mol) was suspended in methanol (500 ml) and water (50 ml) at ambient temperature for 15 minutes. Seed crystals of polymorphic form B of compound 1 (0.50 g, 1.21 mmol) were added. Additional water (50 ml) was added to the suspension and it was shaken at ambient temperature for 18 hours. The mixture was filtered and the filter cake was washed with methanol (50 ml) and dried under vacuum for 3 hours. When x-ray powder diffraction analysis revealed the selected solid substance in the form of polymorphic form B of compound 1 .

The filtrate was combined with a second batch of polymorphic form A of compound 1 (100 g, 0.242 mol), suspended at ambient temperature and seeded with polymorphic form B of the first batch. After shaking at ambient temperature for 18 hours, the mixture was filtered, washed and dried using the same procedure as for batch 1 to form a batch 2 solid. By X-ray powder diffraction analysis, the isolated batch solid 2 was detected as a polymorph form of compound B 1 .

The filtrate of batch 2 was combined with the third batch of polymorphic form A of compound 1 (100 g, 0.242 mol) using the same procedure as for batch 2. The X-ray powder diffraction analysis revealed the isolated solid of batch 3 in the form of polymorphic form B of compound 1 .

The filtrate of batch 3 was combined with the fourth batch of polymorphic form A of compound 1 (109 g, 0.264 mol). Seed crystals of polymorphic form B of the first batch were added. The suspension was shaken at room temperature for 3 hours. The mixture was filtered and the filter cake was washed 9: 1 with methanol / water (200 ml) and dried under vacuum for 3 hours. When x-ray powder diffraction analysis revealed the selected solid substance of party 4 in the form of polymorphic form B of compound 1 . Four batches of polymorphic Form B of compound 1 were combined to form 395 grams (96.6% yield).

PRODUCTION EXAMPLE 4

Synthesis of polymorphic form B of compound 1 (form B)

A solution of sodium acetate (6.01 g, 0.0732 mol) in methanol (30 ml) was treated with methylhydrazine sulfate (5.27 g, 0.0366 mol) at 25 ° C under nitrogen atmosphere. The mixture was heated to 54 ° C for 45 minutes, during which time a thick suspension formed. The mixture was cooled to ambient temperature, filtered through celite, and the insoluble solids were washed with methanol (20 ml). The filtrate was used as follows.

Solution of α-acetyl-2-bromo- N - (2-chloro-6-fluorophenyl) -4-fluorobenzene-ethanethioamide (i.e., product of Production Example 2, Step C) (10.0 g, 0.0229 mol) in toluene (50 ml) was heated to 60 ° C and treated with a solution of methylhydrazine acetate for 30 minutes. Hydrogen sulfide was formed during the addition and was oxidized in a scrubber filled with a disinfectant solution. The mixture was heated for 7 hours and then cooled to 35 ° C. Water (150 ml) was added and the phases were separated. The aqueous phase was extracted with toluene (50 ml) and the combined organic phases were washed with hydrochloric acid (50 ml, 0.1 N) and water (50 ml). The combined organic phases were dried with sodium sulfate, filtered and concentrated under reduced pressure to 30% of the original volume.

The resulting suspension was heated to 50 ° C and treated with seed crystals of polymorphic form B. The agitation was continued for 5 hours and then the suspension was cooled to 30 ° C, treated with heptane (50 ml) and concentrated in vacuo. The resulting thick suspension was diluted with heptane (90 ml), cooled to 5 ° C, shaken for 30 minutes, filtered and the collected solid was dried in a vacuum oven at 50 ° C for 12 hours to form 4- (2-bromo-4- fluorophenyl) - N - (2-chloro-6-fluorophenyl) -1,3-dimethyl-1 H -pyrazol-5-amine (7.6 g). Using x-ray powder diffraction analysis, it was confirmed that the product is a polymorphic form B.

PRODUCTION EXAMPLE 5

Synthesis of polymorphic form B of compound 1 (form B)

To obtain a suspension of compound 1 in toluene, a method identical to the first two paragraphs of Production Example 4 was used. The suspension was diluted with methanol (50 ml) and concentrated to reduce the amount of toluene present. The mixture was diluted with methanol (40 ml), shaken at 25 ° C for 15 minutes, treated with seed crystals of polymorphic form B and shaken for 1 hour. The suspension was further treated with water (10 ml), shaken for 16 hours at 25-27 ° C, filtered and dried in a vacuum oven at 50 ° C for 6 hours with the formation of 4- (2-bromo-4-fluorophenyl) - N - (2-chloro-6-fluorophenyl) -1,3-dimethyl-1 H -pyrazol-5-amine (7.7 g). Using x-ray powder diffraction analysis, it was confirmed that the product is a polymorphic form B.

PRODUCTION EXAMPLE 6

Obtaining polymorphic form B of compound 1 (suspension in toluene)

In a round bottom flask with 4 mouths per 250 ml equipped with a thermocouple, a cold water reflux condenser and a nitrogen inlet, 4.55 g of compound 1 , polymorphic form A (confirmed by pXRD) was added. Toluene (15 g) was added and the resulting suspension was shaken under nitrogen. The mixture was seeded with 0.24 g of polymorphic form B of compound 1 (confirmed by pXRD). The mixture was heated in the range of 43 to 48 ° C. and approximately 2 g of toluene was added to improve mixing. The suspension was shaken for 16.5 hours. The heat source was removed and the contents of the reactor were cooled to room temperature for six hours. The suspension was filtered on filter paper in a Buchner funnel under vacuum. The filter cake was transferred to a drying dish and placed in a vacuum oven at 60 ° C to dry water under vacuum (approximately 18-28 in Hg) overnight. After drying, a white solid (4.6 g) was obtained and pXRD analysis indicated compliance with polymorphic form B.

PRODUCTION EXAMPLE 7

Obtaining polymorphic form B of compound 1 (suspension in toluene)

In a round bottom flask with 4 mouths per 250 ml equipped with a thermocouple, a cold water reflux condenser and a nitrogen inlet, 20.7 g of compound 1 , polymorphic form A (confirmed by pXRD) was added. Toluene (85.1 g) was added and the resulting suspension was shaken under nitrogen. The mixture was seeded using 0.92 g of a sample of compound 1, which is known to be a mixture of polymorphic form A and polymorphic form B. The mixture was heated to 48 ° C for 15 hours. The heat source was removed and the contents of the reactor were cooled to 22 ° C. for 2.5 hours. The suspension was filtered on a large-pore glass funnel under vacuum. The filter cake was transferred to a drying dish and placed in a vacuum oven at 60 ° C to dry water under vacuum (approximately 18-28 in Hg) overnight. A white solid (18.8 g) was obtained and pXRD analysis indicated compliance with polymorphic form B.

PRODUCTION EXAMPLE 8

Obtaining polymorphic form B of compound 1 (suspension in toluene and n heptane)

To a round bottom flask with 4 mouths per 250 ml equipped with a thermocouple, a cold water reflux condenser, an additional funnel and a nitrogen inlet, 12.7 g of compound 1 , polymorphic form A (confirmed by pXRD) was added. The toluene filtrate from Example 5 (60.0 g) was added and the resulting suspension was shaken under nitrogen. The mixture was seeded using 0.27 g of a sample of compound 1, which is known to be a mixture of polymorphic form A and polymorphic form B. The mixture was heated to 51 ° C for 15 hours. The heat source was removed and the contents of the reactor were cooled to 20 ° C. for 3.75 hours. N- heptane (12 g) was added to the suspension dropwise through an additional funnel over 7 minutes. The suspension was shaken for 45 minutes. The resulting suspension was filtered on a large-pore glass funnel under vacuum. The filter cake (15.0 g) was transferred to a drying dish and placed in a vacuum oven at 50 ° C to dry water under vacuum (approximately 18-28 in Hg) overnight. A white solid (14.0 g) was obtained and pXRD analysis indicated compliance with polymorphic form B.

PRODUCTION EXAMPLE 9

The stability of crystalline forms A and B in a liquid composition

The polymorphic form A of compound 1 was obtained as described in Production Example 1. The presence of polymorphic form A was confirmed using pXRD. The Polymorphic Form A of Compound 1 (50 grams) was added to a 1-quart Boston round bottle. Additional ingredients of the composition were weighed into the bottle in the order shown in table 1.

Table 1 Ingredient Function The weight (%) Weight (grams) polymorphic form A of compound 1 technical fungicide 7.57 48.5 fatty acid dimethylamide C ₈ -C ₁₀ primary solvent 62.13 398.0 g 2-ethylhexyl- S- lactate co-solvent 15.3 98.03 ethoxylated castor oil (POE30) nonionic surfactant 7 44.85 ethoxylated propoxylated tristiriphenol (block copolymer) nonionic surfactant 3 19.22 60% calcium dodecylbenzenesulfonate in 2-ethylhexanol anionic surfactant 5 32.03 Total one hundred 640.69

The bottle was closed with a stopper and the contents were shaken using a magnetic stirrer at 20 ° C for 18 hours. Technical fungicide was completely dissolved in the ingredients of the composition. The resulting composition 7EC (emulsifiable concentrate, nominally 70 grams of active substance / liter) was stored at ambient temperature for 35 days. The sample showed visible signs of white solids precipitating from solution. The sample was stored at ambient temperature for an additional 6 months. The composition of the sample was then filtered and white solids were collected. The solids were washed with water and dried in an oven (54 ° C) for 1 hour. The recovered solids led to proton NMR, which corresponded to compound 1 , however, the X-ray powder diffraction spectrum was different from that of polymorphic form A of compound 1 . This was the first appearance of polymorphic form B of compound 1 .

The precipitation of solids of a technical fungicide constitutes an undesirable instability of the composition, which can lead to undesirable effects, such as failure to provide a full degree of bioefficiency or blockage of the equipment used.

EXAMPLE OF DEFINITION OF CHARACTERISTICS 1

X-ray powder diffraction of polymorphic form A of compound 1

) (45 кВ, 40 мА). Данные собирали при комнатной температуре от 3 до 50 градусов 2-тета с применением непрерывного сканирования с эквивалентным размером шага 0,02 градуса и временем счета 320 секунд на шаг в геометрии тета-тета. При необходимости образцы слегка измельчали с помощью агатовой ступки и пестика и получали на держателях для образцов из низкофонового кремния в виде тонкого слоя порошкового материала. Применяли программное обеспечение MDI/Jade версии 9.1 с базой данных Международного комитета по дифракционным данным PDF4+ 2008 для идентификации фаз. Дифракционные максимумы для формы A соединения 1 рассчитывались с помощью операции “Find Peaks” в MDI/Jade и показаны в таблице 2.X-ray powder diffraction was used to identify the crystalline phases of various samples of compound 1 . Data was obtained using a Philips X'PERT Model 3040 automatic powder diffractometer. The diffractometer was equipped with automatic adjustable anti-scatter and divergence slots, an X'Celerator RTMS detector and a Ni filter. The radiation was Cu-K (alpha-1) (λ = 1.54059

) (45 kV, 40 mA). Data was collected at room temperature from 3 to 50 degrees 2-theta using continuous scanning with an equivalent step size of 0.02 degrees and a counting time of 320 seconds per step in theta-theta geometry. If necessary, the samples were slightly crushed using an agate mortar and pestle and obtained on the sample holders made of low-background silicon in the form of a thin layer of powder material. We used MDI / Jade software version 9.1 with the database of the International Committee for Diffraction Data PDF4 + 2008 for phase identification. Diffraction peaks for Form A of compound 1 were calculated using the “Find Peaks” operation in MDI / Jade and are shown in Table 2.

table 2
X-ray diffraction maxima 2θ (in degrees)
for polymorphic form A of compound 1 2θ 2θ 2θ 2θ 2θ 2θ 2θ 6,395 17,067 23,885 29,949 34,329 37,419 40,209 12,035 18,984 24,919 30,834 34,563 37,938 40,577 12,668 19,524 25,352 31,153 35.23 38,357 40,997 13,122 20,573 26.34 31,956 35,636 38,651 14,145 21,194 27,894 32,256 36,134 39,023 14,507 22.23 28,445 32,508 36,385 39,224 14,99 23,215 29,146 33,894 36,836 39.74

DETAILED DESCRIPTION EXAMPLE 2

X-ray powder diffraction pattern for polymorphic form B of compound 1

) (45 кВ, 40 мА). Данные собирали при комнатной температуре от 3 до 50 градусов 2-тета с применением непрерывного сканирования с эквивалентным размером шага 0,02 градуса и временем счета 320 секунд на шаг в геометрии тета-тета. При необходимости образцы слегка измельчали с помощью агатовой ступки и пестика и получали на держателях для образцов из низкофонового кремния в виде тонкого слоя порошкового материала. Применяли программное обеспечение MDI/Jade версии 9.1 с базой данных Международного комитета по дифракционным данным PDF4+ 2008 для идентификации фаз. Дифракционные максимумы для формы B соединения 1 рассчитывались с помощью операции “Find Peaks” в MDI/Jade и показаны в таблице 3.X-ray powder diffraction was used to identify the crystalline phases of various samples of compound 1 . Data was obtained using a Philips X'PERT Model 3040 automatic powder diffractometer. The diffractometer was equipped with automatic adjustable anti-scatter and divergence slots, an X'Celerator RTMS detector and a Ni filter. The radiation was Cu-K (alpha-1) (λ = 1.54059

) (45 kV, 40 mA). Data was collected at room temperature from 3 to 50 degrees 2-theta using continuous scanning with an equivalent step size of 0.02 degrees and a counting time of 320 seconds per step in theta-theta geometry. If necessary, the samples were slightly crushed using an agate mortar and pestle and obtained on the sample holders made of low-background silicon in the form of a thin layer of powder material. We used MDI / Jade software version 9.1 with the database of the International Committee for Diffraction Data PDF4 + 2008 for phase identification. Diffraction maxima for Form B of compound 1 were calculated using the “Find Peaks” operation in MDI / Jade and are shown in Table 3.

Table 3
X-ray diffraction maxima 2θ (in degrees)
for polymorphic form B of compound 1 2θ 2θ 2θ 2θ 2θ 2θ 2θ 8,926 19,938 25.84 30,784 35,654 40,061 44,691 10,894 20,322 26,607 31,439 36,248 40.52 44,954 13,371 20,771 26,977 31,754 36,798 40,663 45,375 14,741 21,694 27,328 32,659 37,085 41,148 46,109 15,361 23,046 27.54 33,364 37,367 41,514 46,897 16,134 23,951 28,394 33,593 37,897 42,734 47.495 16,599 24,285 29,449 34,527 38,676 43,021 48.167 17,199 24,737 29.85 35,097 38,956 43,334 48,632 17,718 25,051 30,467 35,4 39,611 43,632 49.05

DETAILED DESCRIPTION EXAMPLE 3

X-ray diffraction of single crystals for polymorphic form A of compound 1

), и коллиматором MonoCap. В ходе сбора данных кристаллы охлаждали в потоке азота при -100°C.Suitable single crystals for polymorphic form A were grown from methanol evaporation. A colorless disordered plate with approximate dimensions of 0.520 × 0.300 × 0.060 mm was selected for data collection and enclosed in a polymer loop. Single crystal data was collected using a Bruker Platform goniometer with an Apex-II detector. The diffractometer was equipped with an incident beam monochromator using Mo-Kα radiation (λ = 0.71073

), and the MonoCap collimator. During data collection, the crystals were cooled in a stream of nitrogen at -100 ° C.

, b=28,037(16)

, c=7,976(5)

, бета=103,875(10)°, объем=1708,6(17)

³. Пространственную группу определяли как P21/n. Молекулярная масса составляла 412,66 г/моль, что давало рассчитанную плотность 1,604 г/см³, а μ(Mo)=2,59 мм^-1 для Z=4. Обработка данных привела к 3487 уникальным данным в диапазоне два-тета = 5,46-52,92°. Решение и уточнения структуры выполняли при помощи комплекта программ Shelxtl с уточнением на основе F² с коэффициентами рассеяния из Int. Tab. Vol C, таблиц 4.2.6.8 и 6.1.1.4. Конечные уточненные статистические характеристики предусматривают соотношение данные/параметр = 15,57, критерий адекватности по F²=1,06, R-индексы [I>4sigma(I)] R1=0,0564, wR₂=0,1222, R-индексы (все данные) R1=0,0940, wR2=0,1365, максимальные различимые пик и впадина = 0,876 и -0,720 e/

³. Асимметричная единица содержит одну молекулу. Нецелочисленные координаты атомов (×10⁴) и эквивалентные изотропные параметры замещения приведены в таблицах 4 и 5. U(экв.) определяли как одну третью следа ортогонализированного тензора Uij. Предполагаемые стандартные отклонения показаны в круглых скобках.Data was indexed and integrated using the Apex-II software suite, including Sainplus and SADABS. Monoclinic cell parameters were determined as a = 7.870 (5)

, b = 28.037 (16)

, c = 7.976 (5)

, beta = 103.875 (10) °, volume = 1708.6 (17)

³ . The space group was defined as P21 / n. The molecular weight was 412.66 g / mol, which gave a calculated density of 1.604 g / cm ³ and μ (Mo) = 2.59 mm ^-1 for Z = 4. Data processing led to 3487 unique data in the two-theta range = 5.46-52.92 °. The solution and refinement of the structure was performed using the Shelxtl software suite with refinement based on F ² with scattering coefficients from Int. Tab. Vol C, tables 4.2.6.8 and 6.1.1.4. The final refined statistical characteristics include a data / parameter ratio of 15.57, an adequacy criterion for F ² = 1.06, R-indices [I> 4sigma (I)] R1 = 0.0564, wR ₂ = 0.1222, R- indices (all data) R1 = 0.0940, wR2 = 0.1365, maximum distinguishable peak and trough = 0.876 and -0.720 e /

³ . An asymmetric unit contains one molecule. The non-integer atomic coordinates (× 10 ⁴ ) and equivalent isotropic substitution parameters are shown in Tables 4 and 5. U (equiv.) Was determined as one third of the trace of the orthogonalized tensor Uij. Estimated standard deviations are shown in parentheses.

Table 4
Atom coordinates (× 10 ^four ) and equivalent isotropic substitution parameters (A ² × 10 ³ ) for polymorphic form A of compound 1 Atom x y z U (eq.) Cl (1) 2072 (6) 1557 (2) -654 (6) 58 (1) F (1) -4289 (13) 1130 (5) -2620 (16) 58 (1) Cl (1 ') -4627 (5) 1168 (2) -2568 (7) 58 (1) F (1 ') 1813 (14) 1468 (4) -509 (14) 58 (1) Br (1) 1696 (1) 1042 (1) 4113 (1) 73 (1) F (2) -4128 (5) 158 (1) 3495 (5) 100 (1) N (1) -1612 (4) 1819 (1) -1237 (4) 34 (1) N (2) 287 (5) 2573 (1) 2306 (4) 43 (1) N (3) -240 (4) 2454 (1) 603 (4) 38 (1) C (1) -982 (5) 2016 (1) 407 (5) 32 (1) C (2) -926 (5) 1836 (1) 2036 (5) 32 (1) C (3) -115 (5) 2203 (2) 3167 (5) 40 (1) C (4) 244 (7) 2211 (2) 5099 (6) 58 (1) C (5) 28 (6) 2778 (2) -726 (6) 51 (1) C (6) -1267 (6) 1334 (2) -1456 (5) 38 (1) C (7) 442 (6) 1166 (2) -1110 (6) 53 (1) C (8) 853 (10) 687 (2) -1251 (8) 76 (2) C (9) -482 (13) 377 (2) -1772 (8) 92 (2) C (10) -2187 (12) 518 (2) -2198 (7) 86 (2) C (11) -2564 (6) 997 (2) -2047 (6) 58 (1) C (12) -1704 (5) 1390 (1) 2436 (5) 32 (1) C (13) -766 (5) 1015 (2) 3354 (5) 41 (1) C (14) -1575 (7) 597 (2) 3712 (6) 56 (1) C (15) -3332 (7) 564 (2) 3126 (7) 58 (1) C (16) -4350 (6) 914 (2) 2189 (6) 52 (1) C (17) -3540 (5) 1324 (2) 1855 (5) 41 (1)

Table 5
The coordinates of the hydrogen atoms (× 10 ^four ) and equivalent isotropic substitution parameters (A ² × 10 ³ ) for polymorphic form
A compound 1 Atom x y z U (eq.) H (4A) 313 2542 5501 86 H (4B) 1357 2050 5590 86 H (4C) -703 2047 5470 86 H (5A) -1090 2835 -1558 76 H (5B) 860 2637 -1322 76 H (5C) 495 3081 -196 76 H (8A) 2035 582 -989 92 H (9A) -222 47 -1843 111 H (10A) -3099 293 -2591 103 H (14A) -913 345 4348 67 H (16A) -5579 873 1783 62 H (17A) -4227 1572 1217 49 H (1) -2550 (60) 1941 (17) -1720 (60) 47 (14)

DETAILED DESCRIPTION EXAMPLE 4

X-ray diffraction of single crystals for the polymorphic form In compound 1

) и коллиматором MonoCap. В ходе сбора данных кристаллы охлаждали в потоке азота при -100°C.Suitable single crystals for the polymorphic Form B of compound 1 were grown from acetonitrile. A colorless prism with approximate dimensions of 0.480 × 0.260 × 0.260 mm was selected for data collection and enclosed in a polymer loop. Single crystal data was collected using a Bruker Platform goniometer with an Apex-II detector. The diffractometer is equipped with an incident light monochromator using Mo-Kα irradiation (λ = 0.71073

) and the MonoCap collimator. During data collection, the crystals were cooled in a stream of nitrogen at -100 ° C.

, b=11,464(2)

, c=20,010(3)

, объем = 3276,9(10)

³. Пространственную группу определяли как Pbca. Молекулярная масса составляла 412,66 г/моль, что давало рассчитанную плотность 1,673 г/см³, а μ(Mo)=2,70 мм^-1 для Z=8. Обработка данных привела к 3730 уникальным данным в диапазоне два-тета = 4,98-55,04°. Решение и уточнения структуры выполняли при помощи комплекта программ Shelxtl с уточнением на основе F² с коэффициентами рассеяния из, таблиц 4.2.6.8 и 6.1.1.4 Int. Tab. Vol C. Конечные уточненные статистические характеристики предусматривают соотношение данные/параметр = 16,73, критерий адекватности по F² = 1,04, R-индексы [I>4sigma(I)] R1=0,0444, wR2=0,0902, R-индексы (все данные) R1=0,0890, wR2=0,1067, максимальные различимые пик и впадина = 0,538 и -0,466 e/

³. Асимметричная единица содержит одну молекулу. Нецелочисленные координаты атомов (×10⁴) и эквивалентные изотропные параметры замещения приведены в таблицах 6 и 7. U(экв.) определяли как одну третью следа ортогонализированного тензора Uij. Предполагаемые стандартные отклонения показаны в круглых скобках.Data was indexed and integrated using the Apex-II software suite, including Sainplus and SADABS. The parameters of the orthorhombic cell were determined as a = 14.285 (3)

, b = 11,464 (2)

, c = 20.010 (3)

volume = 3276.9 (10)

³ . The space group was defined as Pbca. The molecular weight was 412.66 g / mol, which gave a calculated density of 1.673 g / cm ³ and μ (Mo) = 2.70 mm ^-1 for Z = 8. Data processing led to 3,730 unique data in the two-theta range = 4.98-55.04 °. The solution and refinement of the structure was performed using the Shelxtl software package with refinement based on F ² with scattering coefficients from Tables 4.2.6.8 and 6.1.1.4 Int. Tab. Vol C. The final refined statistical characteristics include a data / parameter ratio of 16.73, an adequacy criterion for F ² = 1.04, R-indices [I> 4sigma (I)] R1 = 0.0444, wR2 = 0.0902, R-indices (all data) R1 = 0.0890, wR2 = 0.1067, maximum distinguishable peak and trough = 0.538 and -0.466 e /

³ . An asymmetric unit contains one molecule. The non-integer atomic coordinates (× 10 ⁴ ) and equivalent isotropic substitution parameters are given in Tables 6 and 7. U (equiv.) Was determined as one third of the trace of the orthogonalized tensor Uij. Estimated standard deviations are shown in parentheses.

Table 6
Atom coordinates (× 10 ^four ) and equivalent isotropic substitution parameters (A ² × 10 ³ ) for the polymorphic form In compound 1 Atom x y z U (eq.) Br (1) 451 (1) 1562 (1) 1480 (1) 43 (1) Cl (1) 4288 (1) 1193 (1) -365 (1) 40 (1) F (1) 4638 (1) 3504 (2) 1767 (1) 39 (1) F (2) 1994 (2) -236 (2) 3569 (1) 47 (1) N (1) 3521 (2) 2304 (2) 861 (1) 24 (1) N (2) 2142 (2) 4872 (2) 1000 (1) 24 (1) N (3) 2840 (2) 4194 (2) 734 (1) 23 (1) C (1) 2923 (2) 3174 (3) 1074 (2) 21 (1) C (2) 2257 (2) 3179 (3) 1572 (2) 22 (1) C (3) 1785 (2) 4250 (3) 1497 (2) 23 (1) C (4) 966 (2) 4681 (3) 1882 (2) 30 (1) C (5) 3326 (3) 4570 (3) 137 (2) 33 (1) C (6) 4487 (2) 2427 (3) 770 (2) 23 (1) C (7) 4948 (2) 1923 (3) 229 (2) 25 (1) C (8) 5908 (3) 2010 (3) 147 (2) 31 (1) C (9) 6431 (2) 2629 (3) 601 (2) 34 (1) C (10) 6003 (2) 3148 (3) 1139 (2) 31 (1) C (11) 5052 (3) 3023 (3) 1218 (2) 26 (1) C (12) 2155 (2) 2280 (3) 2098 (2) 23 (1) C (13) 1417 (2) 1498 (3) 2134 (2) 27 (1) C (14) 1352 (3) 646 (3) 2621 (2) 33 (1) C (15) 2047 (3) 600 (3) 3086 (2) 32 (1) C (16) 2788 (3) 1348 (3) 3094 (2) 34 (1) C (17) 2840 (2) 2190 (3) 2597 (2) 30 (1)

Table 7
The coordinates of the hydrogen atoms (× 10 ^four ) and equivalent isotropic substitution parameters (A ² × 10 ³ ) for polymorphic form
In compound 1 Atom x y z U (eq.) H (4A) 917 5529 1832 44 H (4B) 1047 4487 2356 44 H (4C) 394 4312 1714 44 H (5A) 3559 3886 -106 49 H (5B) 3854 5070 262 49 H (5C) 2895 5008 -150 49 H (8A) 6204 1642 -222 38 H (9A) 7088 2698 543 40 H (10A) 6358 3588 1451 37 H (14A) 843 113 2631 40 H (16A) 3257 1295 3429 40 H (17A) 3352 2717 2594 35 H (1) 3360 (20) 1700 (30) 843 (15) 10 (9)

CHARACTERISTIC DETERMINATION EXAMPLE 5

Temperature-dependent X-ray powder diffraction for the polymorphic form B of compound 1

To assess the stability of the polymorphic form B of compound 1 with respect to temperature, powder X-ray diffraction patterns were obtained by heating a sample of form B from 25 ° C to a temperature exceeding its melting temperature. The measurement was carried out in a 5-IDD synchrotron radiation beam at a synchrotron advanced photon source located at the Argonne National Laboratory (Argonn, Illinois, USA). A differential scanning calorimeter (DSC, model DSC600, Linkam Scientific Instruments, Tadworth, UK) was mounted vertically so that the DSC could be placed under the x-ray beam. DSCs were placed in a synchrotron beam to receive 100-200 square microns of the beam in high vacuum. The standard quartz window was replaced with a polyimide film (Kapton®, 8 μm thick, DuPont, Wilmington, Delaware, USA). An internal thermocouple was installed to record the temperature. A CCD circular detector (model Mar165, diameter 165 mm, Marresearch GmbH, Norderstedt, Germany) was used to detect X-rays scattered by the sample. The detector was equipped with an aluminum cone, which covered the detector and protruded 100 mm above the front surface of the detector. This cone was equipped with a beam absorber substrate and a 5 × 3 mm control beam absorber. The cone was continuously purged with helium to minimize air scattering.

A sample (~ 20 mg) of polymorphic form B of compound 1 was loaded into small aluminum cuvettes with hermetically sealed lids (model Tzero, TA Instruments, New Castle, Delaware, USA). A 5 mm punch was used to tightly fit the sample in place. The sample was slowly compressed using this punch to a level approximately 0.5 mm below the top of the cuvette. The cover was securely installed using a Tzero press with suitable mandrels. A small spring (3-4 turns of fine stainless steel wire at 215 μm, coil diameter of 7 mm) was used to install and center the sample cuvette in the DSC.

The operating parameters during data collection were as follows. The temperature was increased linearly from 25 ° C to 215 ° C at a rate of 10 ° C per minute, then decreased linearly from 215 ° C to 25 ° C at a rate of 20 ° C per minute. The temperature was monitored using a Linkam CI93 temperature control device and an LNP cooling pump. Data was collected using Linkam Linksys32 software. X-ray analysis data was collected simultaneously, but independently. The wavelength was adjusted to 0.07293 nm. The CCD detector was set to high resolution at a pixel size of 79 μm. The distance between the sample and the CCD detector was 115 mm. The exposure time was 0.1 seconds, the frame rate was 1 frame in 10 seconds. The X-ray system was monitored using certified SPEC and APS EPICS research software. The data were preliminarily processed using a macro written to work with SPEC software to translate two-dimensional patterns received from the detector into a standard one-dimensional pXRD pattern, in which the intensity of scattered X-rays and the scattering angle were established. Unidimensional pXRD files were converted to Jade® format for further analysis using MDI / Jade software version 9.1. To establish the pXRD crystal shape, the patterns of the test sample were compared with reference patterns of single crystals of forms A and B, respectively.

Analysis of the pXRD patterns of the test sample indicates that polymorphic form B of compound 1 , heated from room temperature, continues to exist up to 138 ° C when it turns into polymorphic form A. The newly formed polymorphic form A continues to exist until it melts at approximately 160 ° C and above this temperature, the sample structure is absent.

The presence of the conversion of a solid into a solid, below the melting point, upon heating of polymorphic form B indicates an enantiotropic bond between polymorphic forms A and B, i.e. polymorphic form B is more stable below the transition temperature, and polymorphic form A is more stable above the transition temperature.

CHARACTERISTIC DETERMINATION EXAMPLE 6

Relative stability of polymorphic forms A and B of compound 1 at elevated temperature

Form conversion experiments were carried out using several organic solvents and a sample of compound 1, which is known to be a mixture of polymorphic form A and polymorphic form B.

In each experiment, approximately 0.5 g of compound 1 was dispersed in 5-10 ml of solvent in a glass flask with a screw cap with an arm of a magnetic stirrer. The mixture was then shaken at 50 ° C for approximately 100 hours. The mixture was cooled to 20 ° C and then filtered on filter paper in a Buchner funnel under vacuum. The filtered solid was dried in a vacuum oven at 50-60 ° C. for approximately 18 hours and analyzed using pXRD. Table 8 below shows the resulting polymorphic form in accordance with the type of solvent.

Table 8
The polymorphic form obtained by mixing form B of compound 1 in various solvents Solvent The resulting polymorphic form 1-Propanol B Toluene B Methylcyclohexane B n-butyl acetate B

CHARACTERISTIC DETERMINATION EXAMPLE 7

Relative stability of polymorphic forms A and B of compound 1 at elevated temperature

Form conversion experiments were carried out using several organic solvents and a sample of compound 1, which is known to be a mixture of polymorphic form A and polymorphic form B.

In each experiment, approximately 0.7 g of compound 1 was dispersed in 1-4 ml of solvent in a glass flask with a screw cap with an arm of a magnetic stirrer. The mixture was then shaken at 50 ° C for approximately 7 days. The mixture was slowly cooled to 20 ° C and then filtered on filter paper in a Buchner funnel under vacuum. Residual solvent was evaporated in the filtered solids at room temperature for several days. Solids were analyzed using pXRD. Table 9 below shows the resulting polymorphic form in accordance with the type of solvent.

Table 9
The polymorphic form obtained by mixing form B of compound 1 in various solvents Solvent The resulting polymorphic form Tetrahydrofuran B Ethyl acetate B Acetonitrile B

CHARACTERISTIC DETERMINATION EXAMPLE 8

The relative stability of polymorphic forms A and B of compound 1

Form conversion experiments were carried out using a series of solvents and a sample of compound 1 , which is known to be a mixture of polymorphic form A and polymorphic form B.

In each experiment, approximately 0.6-0.8 g of compound 1 was dispersed in 4-10 ml of solvent in a glass flask with a screw cap with an arm of a magnetic stirrer. The mixture was then shaken at 20 ° C for approximately 7 days. The stirrer anchor was removed and the solvent was slowly removed by blowing nitrogen through an unopened vessel for 17 days. Solids were analyzed using pXRD. Table 10 below shows the resulting polymorphic form in accordance with the type of solvent.

Table 10
The polymorphic form obtained by mixing form B of compound 1 in various solvents Solvent The resulting polymorphic form 1-Propanol B Toluene B n-butyl acetate B

EXAMPLE OF DETERMINATION OF CHARACTERISTICS 9

Differential Scanning Calorimetry Experiments

Differential scanning calorimetry was used to study the crystalline phases of various samples of compound 1 . Data was obtained using a TA Instruments Q20-1220 differential scanning calorimeter (V24.2 Build 107) using a standard cell (FC-03859). Samples were obtained by weighing 4-5 mg of compound 1 in a gold-plated bowl (Fauske and Associates, LLC, Burr Ridge, Illinois; part number DSC-M20). The corresponding lid tightly pressed the bowl and the assembled crucible was inserted into the calorimeter. An empty crucible of the same type was prepared in the same manner and inserted as a reference. After starting the instrument, the sample was first balanced at 25 ° C and then heated at a rate of 2 ° C / min to a maximum temperature of 225 ° C.

The DSC thermogram for polymorphic Form A of compound 1 was found to exhibit a sharp endothermic melting with a maximum signal at approximately 168 ° C and a heat of fusion of 78 J / g.

The DSC thermogram for the polymorphic Form B of compound 1 was found to exhibit a wide endothermicity of melting with a maximum signal at about 148 ° C and a heat of fusion of 12 J / g, and a sharp endothermicity of melting with a maximum signal at about 168 ° C and a heat of fusion 75 J / g.

The endothermic transition of polymorphic form B to form A indicates an enantiotropic bond between the two forms, i.e. polymorphic form B is more stable below the transition temperature (approximately 148 ° C), and polymorphic form A is thermodynamically more stable above the transition temperature. This follows from the heat of transition rule (see, for example, R. Hilfiker (ed.), “Polymorphism in the Pharmaceutical Industry”, 2006, Wiley-VCH, Weinheim, Germany).

Composition / Usefulness

The solid form of compound 1 or a mixture (i.e., composition) containing the solid form of compound 1 with (b) at least one fungicidal compound selected from the miscible pairs described in the tables in this document will typically be used to provide fungicidal active ingredients in further compositions, i.e. formulations with at least one additional component selected from the group consisting of surfactants, solid diluents and liquid carriers (i.e., liquid media that carry active and possibly other ingredients; also called liquid diluents). The ingredients of the composition or composition are selected so that they correspond to the physical properties of the active ingredient, the method of application and environmental factors such as soil type, moisture and temperature.

Mixtures of component (a) (i.e., the solid form of compound 1 ) with component (b) (e.g., selected from Table A) and / or one or more other biologically active compounds or agents (c) (i.e., insecticides, other fungicides, nematicides, acaricides, herbicides and other biological agents) can be made using a number of methods, including:

(i) component (a), component (b) and optionally (c) one or more other biologically active compounds or agents can be formulated separately and applied separately or applied simultaneously in a suitable weight ratio, for example, as a tank mixture; or

(ii) component (a), component (b) and optionally (c) one or more other biologically active compounds or agents can be formulated together in a suitable weight ratio.

Suitable formulations include liquid and solid compositions. Liquid compositions include solutions (e.g., emulsifiable concentrates), emulsions (including microemulsions), dispersions and suspensions, and combinations of these forms (e.g., suspoemulsions). The term “suspension”, in particular, refers to a dispersion of particles that have been stabilized by the addition of a chemical additive to minimize or stop the precipitation of the active ingredient. In a dispersion or suspension of particles (for example, in an aqueous suspension concentrate and compositions in the form of an oil dispersion), the liquid carrier forms a continuous liquid phase in which particles (for example, a solid form of compound 1 ) are dispersed or suspended. In a composition in which a suspension or dispersion of particles is combined with an emulsion containing a second (immiscible) liquid (for example, a suspension emulsion composition), the liquid carrier forms a continuous liquid phase in which not only particles are suspended, but other drops are also emulsified (i.e. e. intermittent liquid phase) of the second liquid.

Dispersions and suspensions may be aqueous (i.e. containing mainly water as a liquid carrier) or non-aqueous (i.e. containing water-immiscible organic compounds, commonly referred to as “oil”, as a liquid carrier) in accordance with the nature of the liquid a carrier forming a continuous liquid phase. The main types of aqueous liquid compositions include soluble concentrates, suspension concentrates, capsule suspensions, concentrated emulsions, microemulsions and suspoemulsions. Thus, in suspoemulsions, the liquid carrier that forms the continuous liquid phase is aqueous (i.e., contains water as its main component), and the water-immiscible liquid component is emulsified in the aqueous liquid carrier. The main types of non-aqueous liquid compositions include emulsifiable concentrates, concentrates capable of forming microemulsions, dispersible concentrates and oil dispersions. Suspension concentrates contain particles dispersible in a continuous liquid phase and exist as particle dispersions when added to water. Suspoemulsions and oil dispersions form both particle dispersions and emulsions that coexist when added to water, and one or more of these phases may contain the active ingredient. (In the compositions of the present invention, the particle dispersions contain a solid form of compound 1. )

The main types of solid compositions include pulverulent preparations, powders, granules, pellets, granules, lozenges, tablets, filled films (including seed coatings) and the like, which may be dispersible in water (“wettable”) or water soluble. Films and coatings formed from film-forming liquids are especially applicable for seed treatment in addition to the fact that they are generally used in both liquid and solid types of formulations. The active ingredients can be encapsulated (including microencapsulated) and further formulated in a liquid suspension or dispersion or in a solid composition to protect the active ingredient or for controlled or delayed release of the active ingredient when applied to the target. Alternatively, you can encapsulate (or “cover”) the entire composition, including the active ingredient. By encapsulating, it is also possible to control or slow the release of the active ingredient. Highly concentrated compositions can be prepared and used as intermediates for subsequent use in the preparation of less concentrated liquid and solid formulations.

An embodiment of the composition is noted where the granules of the solid composition containing the solid form of compound 1 are mixed with the granules of the solid composition containing component (b). These mixtures can be further mixed with granules containing one or more additional biologically active compounds or agents, for example, additional agricultural protective agents. Alternatively, two or more agricultural protective agents (e.g., the solid form of compound 1 of component (a), the compound of component (b), agricultural protective agent (c) other than component (a) or (b)) can be combined solid composition from one set of granules, which is then mixed with one or more sets of granules of solid compositions containing one or more additional agricultural protective agents. These granule mixtures may correspond to the general disclosure of the granule mixture from PCT Patent Application Publication No. WO 94/24861 or more preferably a uniform granule mixture from US Pat. No. 6,025,252.

Spray formulations are usually diluted in a suitable medium before spraying. Such liquid and solid formulations are readily dilutable in a spray medium, typically in water. The volumes of the spray solution may vary from about one to several thousand liters per hectare, but more often are in the range from about ten to several hundred liters per hectare. From the sprayed formulations, a tank mixture with water or other suitable medium for treating foliage can be prepared by airborne application or application to the soil or application to a substrate for growing plants. Liquid and dry formulations can be measured directly into drip irrigation systems or measured into a furrow during planting. Liquid and solid formulations can be applied to seeds of crops and other suitable vegetation as seed treatment agents before planting to protect growing roots and other underground parts of the plant and / or foliage by systemic absorption.

Although the solid forms of compound 1 in accordance with the present invention can be used to obtain liquid solutions, emulsifiable concentrates and emulsions by combining with a solvent that dissolves the solid forms, but the solid forms can retain their identity in formulated compositions containing compound 1 as a solid (e.g. particles). Fungicidal compositions in accordance with the present invention, if the composition contains at least one solid form of compound 1, thus include liquid compositions containing compound 1 in the form of a solid (eg, dispersions, suspensions, suspoemulsions), and solid compositions of the compound 1 .

Even though all polymorphic forms and the amorphous solid form of compound 1 can be used to form fungicidal compositions in accordance with the present invention, polymorphic form B is particularly useful for formulating fungicidal compositions, especially liquid compositions, having exceptional physical as well as chemical stability. Although all polymorphic forms and the amorphous solid form of compound 1 are relatively stable (metastable) when isolated and kept at a temperature close to room temperature, they are still thermodynamically unstable compared to polymorphic form B. Therefore, they are naturally transformed into a polymorphic form B. Contact with moisture, exposure to higher temperatures, or for long periods of time may contribute to a more stable crystalline form. Contact with solvents also typically contributes to the conversion of crystalline forms. As a result, liquid compositions containing other polymorphic forms, mixtures of polymorphic forms, or an amorphous solid form of compound 1 are particularly susceptible to spontaneous recrystallization into polymorphic form B. Due to minimal nucleation and slow growth, the formed crystals of polymorphic form B will be relatively small and large. This can lead to both a decrease in biological effectiveness and an increase in the deposition of the active ingredient, since high biological activity and suspendibility depend on the small particle size of the solid active ingredient dispersed in liquid compositions. The use of polymorphic form B for the preparation of compositions for protecting a plant or plant seed from diseases caused by fungal pathogens eliminates the risk of further recrystallization in the compositions. In addition, a composition containing a less stable crystalline form than Form B can change its biological activity during storage, as the ratio of crystalline forms changes. As a rule, this is highly undesirable, since the required operating costs (amount of active ingredient per hectare) will change unpredictably. Accordingly, a composition for protecting a plant or plant seed from diseases caused by the fungal pathogens of the present invention comprising a polymorphic Form B of compound 1 should be noted.

Production Example 9 is an example of an unstable composition obtained from polymorphic form A. An exemplary composition could lead to reduced biological effectiveness due to the loss of active fungicide in the spray composition and / or blockage of the equipment used due to the large particle size of the growing and precipitating solids.

Both liquid and solid formulations containing at least one solid form of compound 1 will typically contain effective amounts of the active ingredient, solid diluent or liquid carrier and surfactant in the following approximate ranges, which add up to 100 weight percent . The general ranges of the amounts of the active ingredient (i.e., the solid form of compound 1 and optionally other active ingredients), diluent and surfactants in the composition in accordance with the present invention containing at least one solid form of compound 1 are as follows.

Weight percent Active
ingredient Diluent Surface-active substance Water-dispersible and water-soluble granules, tablets and powders 0.001-90 0-99,999 0-15 Oil dispersions, suspensions, emulsions, solutions (including emulsifiable concentrates) 1-50 40-99 0-50 Dust preparations 1-25 70-99 0-5 Pellets and pellets 0.001-99 5-99,999 0-15 Concentrated Compositions 90-99 0-10 0-2

Solid diluents include, for example, clays such as bentonite, montmorillonite, attapulgite and kaolin, gypsum, cellulose, titanium dioxide, zinc oxide, starch, dextrin, sugars (e.g. lactose, sucrose), silica, talc, mica, diatomaceous earth, urea, calcium carbonate, sodium carbonate and bicarbonate and sodium sulfate. Typical solid diluents are described in Watkins et al., Handbook of Insecticide Dust Diluents and Carriers , 2nd Ed., Dorland Books, Caldwell, New Jersey.

Liquid diluents include, for example, water, N, N- dimethyl alkanamides (e.g. N, N- dimethylformamide), limonene, dimethyl sulfoxide, N- alkylpyrrolidones (e.g. N- methylpyrrolidinone), ethylene glycol, triethylene glycol, propylene glycol, dipropylene glycol, polypropylene glycol, butylene carbonate, paraffins (e.g. light mineral oils, normal paraffins, isoparaffins), alkylbenzenes, alkylnaphthalenes, glycerin, glycerol triacetate, sorbitol, triacetin, aromatic hydrocarbons, dearomatized aliphatic hydrocarbons s, alkylbenzenes, alkylnaphthalenes, ketones such as cyclohexanone, 2-heptanone, isophorone and 4-hydroxy-4-methyl-2-pentanone, acetates such as isoamyl acetate, hexyl acetate, heptyl acetate, octyl acetate, nonyl acetate, trideacetate and other isoboronyl esters such as alkyl esters of lactic acid, esters of dibasic acids and γ-butyrolactone, and alcohols that may be linear, branched, saturated or unsaturated, such as methanol, ethanol, n- propanol, isopropyl alcohol, n- butanol, isobutyl sleep Hg, n -hexanol, 2-ethylhexanol, n- octanol, decanol, isodecyl alcohol, isooctadecanol, cetyl alcohol, lauryl alcohol, tridecyl alcohol, oleyl alcohol, cyclohexanol, tetrahydrofurfuryl alcohol, diacetone. Liquid diluents also include esters of glycerol and saturated and unsaturated fatty acids (usually C ₆ -C ₂₂ ), such as vegetable seed and fruit oils (e.g. olive oils, castors, flax seeds, sesame seeds, corn (maize), peanuts, sunflowers grape seed, safflower, cottonseed, soybean, rape seed, coconut and coconut kernel), animal fats (e.g. beef tallow, pork tallow, lard, cod liver oil, fish oil) and mixtures thereof. Liquid diluents also include alkylated fatty acids (e.g. methylated, ethylated, bottled), where the fatty acids can be obtained by hydrolysis of glycerol esters from vegetable and animal sources and can be purified by distillation. Typical liquid diluents are described in Marsden, Solvents Guide , 2nd Ed., Interscience, New York, 1950.

Solid and liquid compositions in accordance with the present invention often include one or more surfactants. When added to a liquid, surface-active substances (also known as “surface-active agents”), as a rule, modify, most often reduce, the surface tension of the liquid. Depending on the nature of the hydrophilic and lipophilic groups in the surfactant molecule, surfactants may be useful as wetting agents, dispersing agents, emulsifiers or anti-foaming agents.

Surfactants can be classified as non-ionic, anionic or cationic. Non-ionic surfactants useful for the compositions of the present invention include, but are not limited to, alcohol alkoxylates, such as alcohol alkoxylates based on natural and synthetic alcohols (which may be branched or linear) and derived from alcohols and ethylene oxide, propylene oxide, butylene oxide or mixtures thereof; amine ethoxylates, alkanolamides and ethoxylated alkanolamides; alkoxylated triglycerides, such as ethoxylated soybean, castor and rapeseed oils; alkyl phenol alkoxylates such as octyl phenol ethoxylates, nonyl phenol ethoxylates, dinonyl phenol ethoxylates and dodecyl phenol ethoxylates (derived from phenols and ethylene oxide, propylene oxide, butylene oxide or mixtures thereof); block polymers derived from ethylene oxide or propylene oxide, and “inverted” block polymers in which end blocks are derived from propylene oxide; ethoxylated fatty acids; ethoxylated fatty acid esters and oils; ethoxylated methyl esters; ethoxylated tristyrylphenols (including those derived from ethylene oxide, propylene oxide, butylene oxide, or mixtures thereof); fatty acid esters, glycerol esters, lanolin derivatives, polyethoxylated esters such as polyethoxylated sorbitan fatty acid esters, polyethoxylated sorbitol fatty acid esters and polyethoxylated glycerol fatty acid esters; other sorbitan derivatives, such as sorbitan esters; polymeric surfactants such as random copolymers, block copolymers, PEG (polyethylene glycol) based alkyd resins, grafted or comb polymers and star polymers; polyethylene glycols (PEG); esters of polyethylene glycol and fatty acids; organosilicon surfactants and sugar derivatives such as sucrose esters, alkyl polyglycosides and alkyl polysaccharides.

Suitable anionic surfactants include, but are not limited to, alkylaryl sulfonic acids and their salts; carboxylated ethoxylates of alcohols or alkyl phenols; diphenyl sulfonate derivatives; lignin and lignin derivatives such as lignosulfonates; maleic or succinic acids or their anhydrides; olefinsulfonates; phosphoric acid esters, such as esters of phosphoric acid and alcohol alkoxylates, esters of phosphoric acid and alkyl phenol alkoxylates and esters of phosphoric acid and styryl phenol ethoxylates; protein surfactants; sarcosine derivatives; styrylphenol ether sulfate; sulfates and sulfonates of oils and fatty acids; ethoxylated alkyl phenol sulfates and sulfonates; alcohol sulfates; ethoxylated alcohol sulfates; amine and amide sulfonates, such as N, N- alkyl taurates; sulfonates of benzene, cumene, toluene, xylene and dodecyl and tridecylbenzenes; sulphonates of condensed naphthalenes; naphthalene and alkylnaphthalene sulfonates; sulfonates of fractionated petroleum products; sulfosuccinamates and sulfosuccinates and their derivatives, such as dialkyl sulfosuccinate salts.

Suitable cationic surfactants include, but are not limited to, amides and ethoxylated amides; amines such as N-alkylpropanediamines, tripropylene triamines and dipropylene tetraamines, and ethoxylated amines, ethoxylated diamines and propoxylated amines (derived from amines and ethylene oxide, propylene oxide, butylene oxide or mixtures thereof); amine salts such as aminoacetates and diamine salts; quaternary ammonium salts, such as simple quaternary salts, ethoxylated quaternary salts, and dic Quaternary salts; and amine oxides such as alkyldimethyl amine oxides and bis (2-hydroxyethyl) alkyl amine oxides.

Mixtures of nonionic and anionic surfactants or mixtures of nonionic and cationic surfactants are also applicable to compositions in accordance with the present invention. Non-ionic, anionic and cationic surfactants and their recommended uses are disclosed in a variety of published literature, including McCutcheon's Emulsifiers and Detergents , annual American and international publications published by McCutcheon's Division, The Manufacturing Confectioner Publishing Co .; Sisely and Wood, Encyclopedia of Surface Active Agents , Chemical Publ. Co., Inc., New York, 1964; and AS Davidson and B. Milwidsky, Synthetic Detergents , Seventh Edition, John Wiley and Sons, New York, 1987.

Compositions in accordance with the present invention may also contain excipients and additives for the composition, known to specialists in this field as auxiliary agents for the composition (some of which can be considered as functioning as solid diluents, liquid diluents or surfactants). Such auxiliary substances and additives for the composition can regulate pH (buffers), foaming during production (anti-foaming agents such as polyorganosiloxanes), precipitation of active ingredients (suspending agents), viscosity (thixotropic or pseudoplastic thickeners), growth of microorganisms in containers (antimicrobial agents) , product freezing (antifreeze), color (dispersion of dyes / pigments), rinsing (film-forming agents or adhesives), evaporation (evaporation inhibitors) and other composition properties. Film formers include, for example, polyvinyl acetates, copolymers of polyvinyl acetate, a copolymer of polyvinyl pyrrolidone and vinyl acetate, polyvinyl alcohols, copolymers of polyvinyl alcohols and waxes. Examples of excipients and additives for the composition include those listed in McCutcheon's Volume 2: Functional Materials , annual international and North American publications published by McCutcheon's Division, The Manufacturing Confectioner Publishing Co .; and PCT publication WO 03/024222.

Solid forms of compound 1 and any other active ingredients are usually included in the compositions of the present invention by dissolving the active ingredient in a solvent or grinding in a liquid or dry diluent. Solutions, including emulsifiable concentrates, can be prepared by simply mixing the ingredients. If the solvent of the liquid composition intended for use as an emulsifiable concentrate is not miscible with water, an emulsifier is usually added to emulsify the solvent containing the active substance when diluted with water. Wet grinding of suspensions of the active ingredient with a particle diameter of up to 2000 microns can be carried out using mills for grinding in a medium to obtain particles with an average diameter of less than 3 microns. For suspension concentrates and oil dispersions, a particle size of the active ingredient of 0.1 to 3 microns is required. Prepared suspension concentrates can be obtained from aqueous suspensions (see, for example, US Pat. No. 3,060,084), or they can be spray dried to form water-dispersible granules. For dry compositions, as a rule, dry grinding methods (hammer or air mill) are required, in which particles with an average diameter in the range from 2 to 10 microns are obtained. Particle size can be homogenized by an additional sieving step. Dusty preparations and powders can be obtained by mixing and grinding (for example, using a hammer mill or a jet mill). Granules and pellets can be obtained by spraying the active material onto preformed granular carriers or by sintering procedures. See Browning, “Agglomeration”, Chemical Engineering , December 4, 1967, pages 147-48; Perry's Chemical Engineer's Handbook , 4th Ed., McGraw-Hill, New York, 1963, pages 8-57 et seq., And WO 91/13546. Pellets can be obtained as described in US 4172714. Water-dispersible and water-soluble granules can be obtained as described in US 4144050, US 3920442 and DE 3246493. Tablets can be obtained as described in US 5180587, US 5232701 and US 5208030. Films can be obtained as indicated in GB 2095558 and US 3299566.

The preferred particle size range for the technical solid form of compound 1 is 100-300 μm for ease of handling during filtration and drying. The technical solid form of the compound can then be milled, crushed or sieved to the size needed for the preferred formulation.

The particle size distribution of polymorphic form B can be determined using a particle size analyzer based on laser diffraction, optical light microscopy, or analytical sieving. The particle size distribution parameters D10, D50 and D90 are determined, where D50 represents the median particle size distribution, i.e. 50% of the particles are smaller and 50% are larger than this size. Similarly, D90 means a particle size at which 90% of all particles are smaller than a given size.

Particles of the polymorphic form B 4- (2-bromo-4-fluorophenyl) - N - (2-chloro-6-fluorophenyl) -1,3-dimethyl-1 H -pyrazol-5-amine can be obtained so that they have a distribution the particle size D90 is 500 μm or less or 480 μm or less, or 460 μm or less, or 440 μm or less, or 420 μm or less, or 400 μm or less, or 380 μm or less, or 360 μm or less, or 340 microns or less, or 320 microns or less, or 300 microns or less, or 280 microns or less, or 260 microns or less, or 240 microns or less, or 220 microns or less, or 200 microns or less, or 180 microns or less, or 160 microns or less, or 140 microns or less, or 120 microns or less, or 100 microns or less, or 80 microns or less, or 60 microns or less, or 40 microns or less, or 20 microns or less, or 10 microns or less, or 5 microns or less, or 1 micron or less.

Particles of polymorphic form B can be obtained so that they have a particle size distribution of D50 of 400 μm or less, or 380 μm or less, 360 μm or less, or 340 μm or less, or 320 μm or less, or 300 μm or less, or 280 microns or less, or 260 microns or less, or 240 microns or less, or 220 microns or less, or 200 microns or less, or 180 microns or less, or 160 microns or less, or 140 microns or less, or 120 microns or less, or 100 microns or less, or 80 microns or less, or 70 microns or less, or 60 microns or less, or 50 microns or less, or 45 microns or less, or 40 microns or less, or 35 microns or less or 30 microns or less, or 25 microns or less, or 20 microns or less, or 15 microns or less, or 10 microns or less, or 5 microns or less, or 1 micron or less.

In accordance with the United States Pharmacopeia Convention, the following parameters can be determined based on cumulative distribution. QR (X) = cumulative distribution of particles with a size less than or equal to X (in microns), where R reflects the type of distribution (e.g. 3 for volume). Thus, Q3 (X) = 0.5 if X = X50 (median particle distribution: 50% of the particles are smaller and 50% of the particles are large).

Particles of the polymorphic form B of 4- (2-bromo-4-fluorophenyl) - N - (2-chloro-6-fluorophenyl) -1,3-dimethyl-1 H -pyrazol-5-amine can be obtained so that the cumulative distribution over based on the volume of Q3 (X) (X in microns) Q3 (355) <0.50; or Q3 (180) <0.50 and Q3 (355) ≥ 0.50; or Q3 (125) <0.50 and Q3 (l80) ≥ 0.50; or Q3 (75) <0.50 and Q3 (125) ≥ 0.50; or Q3 (10) <0.50 and Q3 (75) ≥ 0.50; or Q3 (10) ≥ 0.50.

For more information on the area of preparation, see TS Woods, “The Formulator's Toolbox - Product Forms for Modern Agriculture” in the Pesticide Chemistry and Bioscience, The Food-Environment Challenge , T. Brooks and TR Roberts, Eds., Proceedings of the 9th International Congress on Pesticide Chemistry, The Royal Society of Chemistry, Cambridge, 1999, pp. 120-133. See also US 3235361, from column 6, line 16 to column 7, line 19 and examples 10-41; US 3309192, from column 5, lines 43 to column 7, lines 62 and examples 8, 12, 15, 39, 41, 52, 53, 58, 132, 138-140, 162-164, 166, 167 and 169-182 ; US 2891855, from column 3, line 66 to column 5, line 17 and examples 1-4; Klingman, Weed Control as a Science , John Wiley and Sons, Inc., New York, 1961, pages 81-96; Hance et al., Weed Control Handbook , 8th Ed., Blackwell Scientific Publications, Oxford, 1989; and Developments in formulation technology , PJB Publications, Richmond, UK, 2000.

Without further clarification, it is assumed that a person skilled in the art using the preceding description of the composition can use the present invention in full. The following compilation examples, therefore, are regarded as merely illustrative and non-limiting in any way. All percentages are by weight, and all formulations are prepared using conventional methods.

Composition Example A Highly concentrated concentrate Polymorphic Form B of Compound 1 98.5% Silica Airgel 0.5% Synthetic Amorphous Fine Silica 1,0% Composition Example B Wettable Powder Polymorphic Form B of Compound 1 65.0% Polyethylene glycol dodecylphenyl ether 2.0% Sodium ligninsulfonate 4.0% Sodium Aluminosilicate 6.0% Montmorillonite (calcined) 23.0% Composition Example C Granule Polymorphic Form B of Compound 1 10.0% Attapulgite granules (non-volatile, 0.71 / 0.30 mm; US standard sieve No. 25-50) 90.0% Composition Example D Extruded pellet Polymorphic Form B of Compound 1 25.0% Anhydrous Sodium Sulfate 10.0% Crude Calcium Lignosulfonate 5.0% sodium alkylnaphthalenesulfonate 1,0% Calcium Magnesium Bentonite 59.0% Composition Example E Emulsifiable Concentrate Polymorphic Form B of Compound 1 10.0% Polyoxyethylated sorbitanhexaoleate 20.0% C ₆ -C ₁₀ fatty acid methyl ester 70.0% Composition Example F Microemulsion Polymorphic Form B of Compound 1 5.0% Copolymer of polyvinylpyrrolidone and vinyl acetate 30.0% Alkylpolyglycoside 30.0% Glyceryl monooleate 15.0% Water 20.0% Composition Example G Seed treatment Polymorphic Form B of Compound 1 20.00% Copolymer of polyvinylpyrrolidone and vinyl acetate 5.00% Sour Montan Wax 5.00% Calcium Lignosulfonate 1.00% Polyoxyethylene / Polyoxypropylene Block Copolymers 1.00% Stearyl alcohol (POE 20) 2.00% Polyorganosilane 0.20% Colorant - Red Dye 0.05% Water 65.75% Composition Example H Fertilizer stick Polymorphic Form B of Compound 1 2,50% The copolymer of pyrrolidone and styrene 4.80% Tristyrylphenyl Ethoxylate 16 2.30% Talc 0.80% Corn starch 5.00% Slow-acting fertilizer Nitrophoska ^® Permanent 15-9-15 (BASF) 36.00% Kaolin 38.00% Water 10.60% Example I Suspension concentrate Polymorphic Form B of Compound 1 35.0% Block copolymer of butyl polyoxyethylene and polypropylene 4.0% stearic acid / polyethylene glycol copolymer 1,0% styrene acrylic polymer 1,0% xanthan gum 0.1% propylene glycol 5.0% silicone antifoam 0.1% 1,2-benzisothiazolin-3-one 0.1% Water 53.7% Example j Emulsion in water Polymorphic Form B of Compound 1 10.0% block copolymer of butyl polyoxyethylene and polypropylene 4.0% stearic acid / polyethylene glycol copolymer 1,0% styrene acrylic polymer 1,0% xanthan gum 0.1% propylene glycol 5.0% silicone antifoam 0.1% 1,2-benzisothiazolin-3-one 0.1% aromatic hydrocarbon from petroleum feed 20,0 Water 58.7% Example K Dispersion in oil Polymorphic Form B of Compound 1 25.0% Polyoxyethylene sorbitol hexaoleate fifteen% Organically Modified Bentonite Clay 2.5% Fatty Acid Methyl Ester 57.5% Example L Emulsion Polymorphic Form B of Compound 1 15.0% Block copolymer of butyl polyoxyethylene and polypropylene 4.0% stearic acid / polyethylene glycol copolymer 1,0% styrene acrylic polymer 1,0% xanthan gum 0.1% propylene glycol 5.0% silicone antifoam 0.1% 1,2-benzisothiazolin-3-one 0.1% aromatic hydrocarbon from petroleum feed 20.0% Water 53.7%

The compositions are often diluted with water to form aqueous compositions before application. Aqueous compositions for direct application to a plant or part thereof (e.g., compositions in a spray tank) typically contain at least about 1 ppm or more (e.g., 1 ppm to 100 ppm) of the fungicidal active compounds of the present invention.

The compositions of the present invention are useful as a means for controlling plant diseases. The present invention, therefore, further includes a method for controlling plant diseases caused by fungal plant pathogens, comprising applying to the plant or part of it to be protected, or to a plant seed or vegetative propagation unit, to be protected, an effective amount of a composition according to the present invention (e.g., composition containing component (a), or components (a) and (b), or components (a), (b) and (c)). This aspect of the present invention can also be described as a method of protecting a plant or plant seed from diseases caused by fungal pathogens, comprising applying a fungicidally effective amount of the composition of the present invention to a plant (or part thereof) or a plant seed (directly or through the environment (e.g., environment for growing) a plant or plant seed).

The solid form of compound 1 of component (a) with compounds of component (b) and / or (c) with one or more biologically active compounds or agents can be applied to plants (i.e., agronomic and non-agronomic) that contain genetic material introduced using genetic engineering (i.e. transgenic) or modified by mutagenesis to provide useful traits. Examples of such traits include herbicide tolerance, resistance to herbivorous pests (e.g. insects, ticks, aphids, spiders, hookworms, snails, phytopathogenic fungi, bacteria and viruses), improved plant growth, and increased tolerance to adverse growing conditions, such as high or low temperatures, low or high soil moisture and severe salinity, increased flowering or fruiting, increased harvest, accelerated ripening, improved quality and / or nutritional value with a collected product or an improvement in the storage or processing ability of the collected products. Transgenic plants can be modified to express several traits. Examples of plants having traits provided by genetic engineering or mutagenesis include varieties of corn, cotton, soybean and potato expressing an insecticidal toxin of Bacillus thuringiensis, such as ^{YIELD GARD ®, KNOCKOUT ®, STARLINK} ®, BOLLGARD ®, NuCOTN ® and NEWLEAF ^®, and herbicide tolerant varieties of corn, cotton, soybean and rapeseed, such as ROUNDUP READY ^® , LIBERTY LINK ^® , IMI ^® , STS ^® and CLEARFIELD ^® , as well as cultures expressing N- acetyltransferase (GAT), providing resistance to the glyphosate herbicide, or cultures containing the HRA gene providing resistance to the coat of arms tsidam inhibiting acetolactate synthase (ALS). The solid forms of compound 1 and their compositions can synergistically affect traits introduced by genetic engineering or modified by mutagenesis, thereby enhancing phenotypic expression or trait efficiency or increasing the efficiency of plant disease control using the compounds and compositions of the present invention. In particular, the solid forms of compound 1 and their compositions can synergistically affect the phenotypic expression of proteins or other natural products that are toxic to fungal pathogens to provide a control effect of the fungal disease in excess of the additive.

The compositions of the present invention may also optionally contain plant nutrients, for example, when the fertilizer composition contains at least one plant nutrient selected from nitrogen, phosphorus, potassium, sulfur, calcium, magnesium, iron, copper, boron, manganese, zinc and molybdenum. It should be noted compositions comprising at least one fertilizer composition containing at least one plant nutrient selected from nitrogen, phosphorus, potassium, sulfur, calcium and magnesium. The compositions of the present invention, which further comprise at least one plant nutrient, may be in the form of liquids or solids. It should be noted solid formulations in the form of granules, small sticks or tablets. Solid formulations containing a fertilizer composition can be prepared by mixing the compound or composition of the present invention with the fertilizer composition together with the constituent ingredients and then preparing the composition using methods such as granulation or extrusion. Alternatively, solid formulations can be prepared by spraying a solution or suspension of a compound or composition of the present invention in a volatile solvent onto a previously prepared fertilizer composition in the form of non-shrink mixtures, for example, granules, small sticks or tablets, and then evaporating the solvent.

Plant disease control is usually accompanied by the application of an effective amount of a composition according to the present invention (for example, containing component (a) or a mixture of components (a), (b) and optionally (c)), usually in the form of a composition either before or after infection , on the part of the plant to be protected, such as roots, stems, foliage, fruits, seeds, tubers or bulbs, or on the medium (soil or sand) in which the plants to be protected are grown. Component (a) or mixtures thereof can also be applied to seeds to protect seeds and seedlings that develop from seeds. For processing plants, mixtures can also be applied through irrigation water. The control of pathogens that are active after harvest, which infect the products before harvest, is usually carried out by applying the composition according to the present invention in the field, and if the infection occurs after harvest, the composition can be applied to the harvested crop plants as impregnation, sprayed solutions, fumigation products, processed wrappers or liners in boxes.

Suitable application rates (e.g., fungicidally effective amounts) of component (a) (i.e., solid form of compound 1 ), as well as suitable application rates (e.g., biologically effective amounts, fungicidally effective amounts or insecticidally effective amounts) of components (b) and optionally (c) according to the present invention, many environmental factors can influence, and should be determined under actual conditions of use. Foliage can usually be protected at a processing rate of from less than about 1 g / ha to about 5000 g / ha of active ingredients. Seed and seedlings can usually be protected with a seed treatment rate of from about 0.1 to about 10 g per kilogram of seeds; and vegetative propagation units (eg, layering and tubers) can usually be protected at a processing rate of the propagation unit of from about 0.1 to about 10 g per kilogram of propagation unit. One of skill in the art can easily determine, through a simple experiment, the application rates of component (a), its mixtures and compositions containing specific combinations of the active ingredients of the present invention necessary to provide the desired spectrum of plant protection, control of plant diseases, and optionally other plant pests.

The solid forms of compound 1 are particularly effective for controlling plant diseases caused by fungal pathogens, in particular from the classes Basidomycete and Ascomycete. By combining these compounds with other fungicidal compounds, it is possible to control diseases caused by a wide range of fungal plant pathogens from the classes Basidiomycete, Ascomycete, Oomycete and Deuteromycete. Accordingly, using the mixtures and compositions described in this document, it is possible to control a wide range of plant diseases, pathogens of leaves of agricultural crops, including cereal crops, such as wheat, barley, oats, rye, triticale, rice, maize, sorghum and millet; vine crops, such as table and wine grapes; field crops such as oilseed rape (canola), sunflower; sugar beets, sugarcane, soybeans, peanuts (peanuts), tobacco, alfalfa, clover, woodpecker, shamrock and vetch; fruit seeds such as apple, pear, wild apple, lokva, hawthorn and quince; stone fruit, such as peaches, cherries, plums, apricots, nectarines and almonds; fruit citrus fruits such as lemons, lime, oranges, grapefruit, mandarin (tangerines) and kumquat; root and tuberous vegetable crops and field crops (and their foliage), such as artichoke, table and sugar beets, carrots, cassava, ginger, ginseng, horseradish, parsnips, potatoes, radishes, rutabaga, sweet potatoes, turnips and yams; onion vegetable crops such as garlic, leeks, onions and shallots; green vegetable crops such as arugula (eruca), celery, watercress, endive (escariol), fennel, head and leaf lettuce, parsley, radicchio (red chicory), rhubarb, spinach and beetroot; cabbage (headed) leafy vegetable crops, such as broccoli, field cabbage (rape), Brussels sprouts, garden cabbage, Chinese cabbage, cauliflower, braunkol, fodder cabbage, kohlrabi, mustard and greens; legumes of vegetable crops (juicy or dried), such as lupine, beans ( Phaseolus spp.) (including fodder beans, ordinary beans, lima beans, Turkish beans, pinto beans, multicolor beans, husked varieties of beans, tepari and wax beans) , beans ( Vigna spp.) (including adzuki, vigna, dolichos round seed, pigeon peas, Chinese long beans, laguta, coarse vigna, mott, mung bean, rice bean, Chinese vigna, urid bean and cow peas), horse beans ( fava), chickpea (garbanzo beans), hyuar, Jack bean, Lablab, lentil and pea (Pisum spp.) (in including low ohm peas, peas, sugar and vegetable garden, peas, English, field pea, garden pea, pea, peas in the pod, peas, sugar, and soy Kajanus); fruit vegetables such as eggplant, physalis ( Physalis spp.), pepino and pepper (including salad pepper, hot pepper, table pepper, allspice, sweet pepper); Mexican tomato and tomato; pumpkin vegetable crops, such as chayote (fruits), Chinese wax gourd (winter melon), fodder watermelon, cucumber, anguria, edible bottle gourd (including lagenaria, corn, luffa and spikelet loofah), Momordica spp. (including balsamic momordica, havarence momordica, bitter melon and Chinese cucumber), cantaloupe melon (including cantaloupe and pumpkin), common pumpkin and large-fruited pumpkin (including nutmeg pumpkin, fodder pumpkin, giant pumpkin, acorn pumpkin, pumpkin -spaghetti) and watermelon; berries such as blackberries (including bingleberry, bozenberry, blackberry, lowberry, marionberry, olallieberry and youngberry), blueberries, cranberries, currants, elderberries, gooseberries , blueberries, logan berries, raspberries and strawberries; walnut trees such as almonds, beech nuts, American walnuts, gray walnuts, Western cashews, edible chestnuts, dwarf chestnuts, hazelnuts, hazelnuts, macadamia nuts, brown pecans and walnuts; tropical fruit crops and other crops such as bananas, edible bananas, mangoes, coconuts, papaya, guayava, avocado, lychee, agave, coffee tree, cocoa tree, sugarcane, oil palm, sesame, hevea and spices; fibrous crops such as cotton, flax and hemp; lawn grasses (including lawn grasses for the warm and cold season), such as a field grass, meadow bluegrass, Augustinian grass, reed fescue and Bermuda grass.

These pathogens include Oomycetes, including pathogens from the genusPhytophthora, such asPhytophthora infestans,Phytophthora megasperma,Phytophthora parasitica,Phytophthora cinnamomi andPhytophthora capsicipathogens of the genusPythium, such asPythium aphanidermatum, and pathogens from the Peronosporaceae family, such asPlasmopara viticola,Peronospora spp.(includingPeronospora tabacinaandPeronospora parasitica),Pseudoperonosporaspp. (includingPseudoperonospora cubensis) andBremia lactucae; Ascomycetes, including pathogens from the genusAlternaria, such asAlternaria solani andAlternaria brassicaepathogens of the genusGuignardia, such asGuignardia bidwellipathogens of the genusVenturia, such asVenturia inaequalispathogens of the genusSeptoria, such asSeptoria nodorumandSeptoria tritici, powdery mildew pathogens such asBlumeria spp. (includingBlumeria graminis) andErysiphe spp. (includingErysiphe polygoni),Uncinula necatur,Sphaerotheca fuliginea andPodosphaera leucotricha,Pseudocercosporella herpotrichoidespathogens of the genusBotrytis,such asBotrytis cinerea,Monilinia fructicolapathogens of the genusSclerotinia, such asSclerotinia sclerotiorum andSclerotinia minor,Magnaporthe grisea,Phomopsis viticolapathogens of the genusHelminthosporium, such asHelminthosporium tritici repentis,Pyrenophora terespathogens causing anthracnose disease such asGlomerellaorColototrichumspp. (such asColletotrichum graminicolaandColletotrichum orbiculare) andGaeumannomyces graminis; Basidiomycetes, including rust diseases caused byPuccinia spp. (such asPuccinia recondita,Puccinia striiformis,Puccinia hordei,Puccinia graminis andPuccinia arachidis),Hemileia vastatrix andPhakopsora pachyrhizi; other pathogens, including Rhizoctonia spp. (such asRhizoctonia solani and Rhizoctonia oryzae); pathogens of the genusFusarium, such asFusarium roseum,Fusarium graminearum andFusarium oxysporum;Verticillium dahliae;Sclerotium rolfsii;Rynchosporium secalis;Cercosporidium personatum,Cercospora arachidicola andCercospora beticola; Rutstroemia floccosum(also known asSclerontina homoeocarpa);Rhizopus spp. (such asRhizopus stolonifer);Aspergillus spp. (such asAspergillus flavus andAspergillus parasiticus); and other genera and species closely related to these pathogens. Usually pathogens are considered as diseases, and thus, in the previous sentence, the word “pathogen” also refers to a plant disease caused by a pathogen. More precisely, plant diseases are caused by pathogens. Therefore, for example, powdery mildew is a plant disease caused by pathogens of powdery mildew, diseases caused bySeptoriaare plant diseases caused by pathogensSeptoriaand rusts are plant diseases caused by rust pathogens. Certain fungicidal compounds are also bactericidal, and therefore, in addition to their fungicidal activity, the composition or combination may also have activity against bacteria, such asErwinia amylovora,Xanthomonas campestris,Pseudomonas syringae and other related species. In addition, solid forms of the compoundone and their mixtures and compositions according to the present invention are applicable in the treatment of diseases that occur after harvest on fruits and vegetables caused by fungi and bacteria. These infections can occur before, during, and after harvest. For example, infections can occur before harvest, and then remain inactive until some point in time during maturation (for example, the host begins such changes in the tissues that the infection can develop); infections can also arise from superficial wounds resulting from mechanical or insect damage. In this regard, the application of the compounds, mixtures and compositions of the present invention can reduce losses (i.e., losses in terms of quantity and quality) due to post-harvest diseases that can occur at any time from harvest to consumption. The treatment of post-harvest diseases by the compounds of the present invention can increase the period of time during which perishable edible parts of plants (e.g., fruits, seeds, foliage, stems, bulbs, tubers) can be stored frozen or unfrozen after harvest, and at the same time, they remain edible and do not have noticeable or harmful destruction or contamination by fungi or other microorganisms. Treating the edible parts of plants before or after harvesting with the compounds, mixtures or compositions of the present invention also reduces the formation of toxic metabolites of fungi or microorganisms, for example, mycotoxins, such as aflatoxins.

In the fungicidal compositions of the present invention, the solid forms of compound 1 of component (a) can work synergistically with additional fungicidal compounds of component (b) to provide beneficial effects such as expanding the spectrum of controlled plant diseases, increasing the duration of prophylactic and therapeutic protection, and suppressing the multiplication of resistant fungal pathogens . In specific embodiments, compositions of the present invention are provided that contain fractions of component (a) and component (b) that are particularly useful for controlling specific fungal diseases (such as Alternaria solani , Blumeria graminis f. Sp. Tritici , Botrytis cinerea , Puccinia recondita f. Sp. Tritici , Rhizoctonia solani , Septoria nodorum , Septoria tritici ).

Mixtures of fungicides can also provide significantly better control of plant diseases than could be predicted based on the activity of individual components. This synergy has been described as “such a combined effect of two components of a mixture in which the overall effect is greater or longer than the sum of the effects of two (or more) taken independently” (see PML Tames, Neth. J. Plant Pathology , 1964 , 70 , 73-80). In methods for controlling plant diseases in which a synergy effect is exerted by a combination of active ingredients (e.g. fungicidal compounds) applied to a plant or seed, the active ingredients being applied in a synergistic weight ratio and synergistic (i.e. synergistically effective) amounts. Disease control, suppression and prevention indicators cannot exceed 100%. Therefore, the expression of significant synergism, as a rule, requires the application of active ingredients, in which the active ingredients individually provide an effect much less than 100%, so that their total effect is significantly less than 100%, which makes it possible to increase the effect as a result of synergism. On the other hand, application rates for active ingredients that are too low may not show much activity in mixtures even with the advantage of synergism. A person skilled in the art can easily determine and optimize weight ratios and application rates (i.e., amounts) of fungicidal compounds providing a synergy effect through a simple experiment.

Solid forms of compound 1 can also be mixed with one or more other biologically active compounds or agents, including insecticides, fungicides, nematicides, bactericides, acaricides, herbicides, herbicide antidotes, growth regulators such as insect molting inhibitors and rooting stimulants, chemostimulants, chemical signaling substances, repellents, attractants, pheromones, nutrition stimulants, other biologically active compounds or entomopathogenic bacteria, viruses or fungi, with the formation of a multicomponent pesticide with an even wider range of agronomic and non-agronomic usefulness.

It should be noted a composition which, in addition to the solid forms of compound 1 of component (a), includes as component (b) at least one fungicidal compound selected from the group consisting of classes (b1) of methylbenzimidazole carbamate (MBC) fungicides; (b2) dicarboximide-based fungicides; (b3) demethylation inhibitor fungicides (DMI); (b4) phenylamide-based fungicides; (b5) amine / morpholine fungicides; (b6) phospholipid biosynthesis inhibitor fungicides; (b7) carboximide-based fungicides; (b8) hydroxy (2-amino) pyrimidine fungicides; (b9) anilinopyrimidine-based fungicides; (b10) N- phenylcarbamate-based fungicides; (b11) external quinone-binding site (QoI) fungicide inhibitors; (b12) phenylpyrrole-based fungicides; (b13) quinoline-based fungicides; (b14) lipid peroxidation inhibitor fungicides; (b15) fungicides inhibitors of melanin biosynthesis, affecting reductase (MBI-R); (b16) fungicides inhibitors of melanin biosynthesis, affecting dehydratase (MBI-D); (b17) hydroxyanilide-based fungicides; (b18) squalene epoxidase inhibitor fungicides; (b19) polyoxin-based fungicides; (b20) phenylurea-based fungicides; (b21) fungicides inhibitors of the internal quinone binding site (QiI); (b22) benzamide-based fungicides; (b23) enopyiranuronic acid antibiotic fungicides; (b24) hexapyranosyl antibiotic fungicides; (b25) glucopyranosyl-based antibiotic fungicides that affect protein synthesis; (b26) glucopyranosyl-based antibiotic fungicides affecting trehalase and inositol biosynthesis; (b27) cyanoacetamidoxime-based fungicides; (b28) carbamate-based fungicides; (b29) fungicides that decompose oxidative phosphorylation; (b30) organic tin fungicides; (b31) carboxylic acid fungicides; (b32) heteroatom-based fungicides; (b33) phosphonate-based fungicides; (b34) phthalamic acid fungicides; (b35) benzotriazine-based fungicides; (b36) benzene sulfonamide fungicides; (b37) pyridazinone-based fungicides; (b38) thiophene-carboxamide-based fungicides; (b39) pyrimidinamide-based fungicides; (b40) carboxylic acid amide fungicides (CAA); (b41) tetracycline-based antibiotic fungicides; (b42) thiocarbamate-based fungicides; (b43) benzamide-based fungicides; (b44) fungicides inducing protection of the host plant; (b45) fungicides with contact activity acting on multiple sites; (b46) fungicides other than fungicides of classes (b1) to (b45); and salts of compounds of classes (b1) to (b46).

Further descriptions of these classes of fungicidal compounds are provided below.

(b1) “Methylbenzimidazole carbamate-based fungicides (MBC)” (FRAC (International Committee for the Resistance to Fungicides) code 1) inhibit mitosis by binding to β-tubulin during microtubule assembly. Inhibition of microtubule assembly can interfere with cell division, intra-cell transport, and cell structure. Methylbenzimidazole carbamate fungicides include benzimidazole and thiophanate fungicides. Benzimidazoles include benomyl, carbendazim, fuberidazole and thiabendazole. Thiophanates include thiophanate and thiophanate methyl.

(b2) “Dicarboximide-based fungicides” (FRAC code 2) are thought to inhibit lipid peroxidation in fungi by exposing NADH to cytochrome reductase. Examples include chlozolinate, iprodion, procymidone and vinclozolin.

(b3) “Demethylation Inhibitor Fungicides (DMI)” (FRAC code 3) inhibit C ₁₄ demethylase, which plays a role in the production of sterols. Sterols, such as ergosterol, are necessary for the structure and function of the membrane, which makes them indispensable for the development of functional cell walls. Therefore, exposure to these fungicides leads to abnormal growth and, ultimately, to the death of susceptible fungi. DMI fungicides come from several chemical classes: azoles (including triazoles and imidazoles), pyrimidines, piperazines and pyridines. Triazoles include azaconazole, bitertanol, bromukonazole, ciproconazole, diphenoconazole, diniconazole (including diniconazole-M), epoxiconazole, ethaconazole, fenbuconazole, fluquinconazole, fluzylazole azonazonazoleazonazoleazonazoleazonazoleazonazoleazonazoleazonazoleazonazoleazonazoleazonazoleazonazole, quinconazole, simeconazole, tebuconazole, tetraconazole, triadimefon, triadimenol, triticonazole and uniconazole. Imidazoles include clotrimazole, econazole, imazalil, isoconazole, miconazole, oxpoconazole, prochlorase, pefurazoate and triflumisole. Pyrimidines include phenarimol, nuarimol and triarimol. Piperazines include triforin. Pyridines include butiobate and pyrifenox. Biochemical studies have shown that all of the above fungicides belong to DMI fungicides, as described by KH Kuck et al. in Modern Selective Fungicides - Properties, Applications and Mechanisms of Action , H. Lyr (Ed.), Gustav Fischer Verlag: New York, 1995, 205-258.

(b4) “Phenylamide-based fungicides” (FRAC code 4) are specific RNA polymerase inhibitors in Oomycete class fungi. Sensitive fungi exposed to these fungicides exhibit reduced ability to incorporate uridine into rRNA. The growth and development of sensitive fungi is prevented by exposure to this class of fungicides. Phenylamide fungicides include acylalanine, oxazolidinone and butyrolactone fungicides. Acylalanines include benalaxyl, benalaxyl-M, furalaxyl, metalaxyl, metalaxyl-M (also known as mefenoxam). Oxazolidinones include oxadixyl. Butyrolactones include ofuras.

(b5) “Amine / morpholine-based fungicides” (FRAC code 5) inhibit two target sites in the biosynthetic pathway of sterols, δ ⁸ → δ ⁷ isomerase and δ ¹⁴ reductase. Sterols, such as ergosterol, are necessary for the structure and function of the membrane, which makes them indispensable for the development of functional cell walls. Therefore, exposure to these fungicides leads to abnormal growth and, ultimately, to the death of susceptible fungi. Amine / morpholine-based fungicides (also known as non-DMI sterol biosynthesis inhibitors) include morpholine, piperidine and spiroketal amine fungicides. Morpholines include aldimorph, dodemorph, fenpropimorph, tridemorph and trimorphamide. Piperidines include phenpropidine and piperaline. Spiroketal amines include spiroxamine.

(b6) “Phospholipid biosynthesis inhibitor fungicides” (FRAC code 6) inhibit the growth of fungi by affecting the phospholipid biosynthesis. Fungicides acting on the biosynthesis of phospholipids include phosphorothiolate and dithiolan fungicides. Phosphorothiolates include edifenfos, iprobenfos and pyrazophos. Dithiolans include isoprothiolan.

(b7) “Carboxamide-based fungicides” (FRAC code 7) inhibit fungal respiratory chain complex II (succinate dehydrogenase) by breaking down a key enzyme in the Krebs cycle (CTK cycle) called succinate dehydrogenase. Inhibition of respiration prevents the formation of ATP in the fungus and thus inhibits growth and reproduction. Carboxamide fungicides include benzamide, furancarboxamide, oxathinecarboxamide, thiazolecarboxamide, pyrazolecarboxamide and pyridinecarboxamide. Benzamides include benodanil, flutolanil and mepronil. Furancarboxamides include fenfuram. Oksatinikarboksamidy include carboxin and oxycarboxin. Thiazolecarboxamides include tiflusamide. Pyrazolecarboxamides include bixafen, furametpir, isopyrazam, fluxapiroxad, sedaxan ( N - [2- (1 S , 2 R ) - [1,1'-bicyclopropyl] -2-ylphenyl] -3- (difluoromethyl) -1-methyl-1 H- pyrazole-4-carboxamide) and penflufen ( N - [2- (1,3-dimethylbutyl) phenyl] -5-fluoro-1,3-dimethyl-1 H -pyrazole-4-carboxamide (PCT Patent Publication WO 2003 / 010149)). Pyridinecarboxamides include boscalide.

(b8) “Hydroxy (2-amino) pyrimidine-based fungicides” (FRAC code 8) inhibit the synthesis of nucleic acids by acting on adenosine deaminase. Examples include bupirimat, dimethyrimol, and etirimol.

(b9) “Anilinopyrimidine-based fungicides” (FRAC code 9) are believed to inhibit the biosynthesis of the amino acid methionine and disrupt the secretion of hydrolytic enzymes that lyse plant cells during infection. Examples include cyprodinil, mepanipyrim, and pyrimethanil.

(b10) “ N- phenylcarbamate-based fungicides” (FRAC code 10) inhibit mitosis by binding of β-tubulin and disruption of microtubule assembly. Inhibition of microtubule assembly can interfere with cell division, intra-cell transport, and cell structure. Examples include diethocarb.

(b11) “External quinone binding site (QoI) inhibitor fungicides” (FRAC code 11) inhibit mitochondrial respiration complex III in fungi by acting on ubiquinol oxidase. The oxidation of ubiquinol is blocked at the site of the “external quinone-binding site” (Qo) of the cytochrome bc 1 complex, which is located in the inner membrane of the mitochondria of the fungi. Inhibition of the mitochondrial respiratory chain interferes with the normal growth and development of fungi. Inhibitors of the external quinone-binding site (also known as strobilurin-based fungicides) include methoxyacrylate, methoxycarbamate, oximinoacetate, oximinoacetamide, oxazolidinedione, dihydrodioxazine, imidazolinone and benzyl carbamide. Methoxyacrylates include azoxystrobin, enestroburin (SYP-Z071) and picoxystrobin. Methoxycarbamates include pyraclostrobin and pyramethostrobin. Oximinoacetates include kresoxim-methyl, pyraxystrobin and trifloxystrobin. Oxyiminoacetamides include dimoxystrobin, metominostrobin, oryzastrobin, α- [methoxyimino] - N- methyl-2 - [[[1- [3- (trifluoromethyl) phenyl] ethoxy] imino] methyl] benzene acetamide and 2 - [[[3- (2 , 6-dichlorophenyl) -1-methyl-2-propen-1-ylidene] amino] oxy] methyl] -α- (methoxyimino) -N- methylbenzeneacetamide. Oxazolidinediones include famoxadone. Dihydrodioxazines include fluoxastrobin. Imidazolinones include phenamidone. Benzyl carbamates include pyribencarb.

(b12) “Phenylpyrrole-based fungicides” (FRAC code 12) inhibit the MAP protein kinase associated with osmotic signal transduction in fungi. Fenpiclonil and fludioxonil are examples of this class of fungicides.

(b13) “Quinoline-based fungicides” (FRAC code 13) are thought to inhibit signal transduction by acting on G proteins in early cell signaling. As shown, they prevent the germination and / or formation of an appressorium in fungi that cause real powdery mildew. Quinoxifene is an example of this class of fungicides.

(b14) “Lipid peroxidation inhibitor fungicides” (FRAC code 14) are believed to inhibit lipid peroxidation, which interferes with membrane synthesis in fungi. Representatives of this class, such as ethridiazole, can also interfere with other biological processes, such as respiration and the biosynthesis of melanin. Fungicides acting on lipid peroxidation include aromatic hydrocarbon-based fungicides and 1,2,4-thiadiazole fungicides. Aromatic hydrocarbon based fungicides include biphenyl, chloroneb, dicloran, quintozene, teknazene, and tolclofos-methyl. 1,2,4-thiadiazole-based fungicides include ethridiazole.

(b15) “Fungicides inhibitors of melanin biosynthesis affecting reductase (MBI-R)” (FRAC code 16.1) inhibit the naphthale reduction step in melanin biosynthesis. Melanin is required to infect the host plant with certain fungi. Melanin biosynthesis inhibitor fungicides that affect reductase include isobenzofuranone, pyrroquinolinone and triazolobenzothiazole fungicides. Isobenzofuranones include phthalide. Pyrroquinolinolones include pyroquilone. Triazolobenzothiazoles include tricyclazole.

(b16) “Melanin biosynthesis inhibitor fungicides affecting dehydratase (MBI-D)” (FRAC code 16.2) inhibit scitalalone dehydratase in melanin biosynthesis. Melanin is required to infect the host plant with certain fungi. Melanin biosynthesis inhibitor fungicides affecting dehydratase include cyclopropanecarboxamide, carboxamide and propionamide fungicides. Cyclopropanecarboxamides include Carpropamide. Carboxamides include diclocimet. Propionamides include phenoxanil.

(b17) “Hydroxyanilide-based fungicides (FRAC code 17) inhibit C4 demethylase, which plays a role in the formation of sterols. Examples include phenhexamide.

(b18) “Squalene epoxidase inhibitor fungicides” (FRAC code 18) inhibit squalene epoxidase in the ergosterol biosynthesis pathway. Sterols, such as ergosterol, are necessary for the structure and function of the membrane, which makes them indispensable for the development of functional cell walls. Therefore, exposure to these fungicides leads to abnormal growth and, ultimately, to the death of susceptible fungi. Squalene epoxidase inhibitor fungicides include thiocarbamate and allylamine fungicides. Thiocarbamates include piributicarb. Allylamines include naftifin and terbinafine.

(b19) “Polyoxin-based fungicides” (FRAC code 19) inhibit chitin synthase. Examples include polyoxin.

(b20) “Phenylurea-based fungicides” (FRAC code 20) are believed to disrupt cell division. Examples include pencicuron.

(b21) “Inhibitors of the internal quinone-binding site (QiI)” (FRAC code 21) inhibit the mitochondrial respiration complex III in fungi by acting on ubiquinol reductase. Ubiquinol reduction is blocked at the site of the “internal quinone-binding site” (Qi) of the cytochrome bc 1 complex, which is located in the inner membrane of the mitochondria of the fungi. Inhibition of the mitochondrial respiratory chain interferes with the normal growth and development of fungi. Inhibitors of the internal quinone binding site include cyanoimidazole and sulfamoyl triazole fungicides. Cyanoimidazoles include cyazofamide. Sulfamoyl triazoles include amisulbrom.

(b22) “Benzamide-based fungicides” (FRAC code 22) inhibit mitosis by binding to β-tubulin and impaired microtubule assembly. Inhibition of microtubule assembly can interfere with cell division, intra-cell transport, and cell structure. Examples include zoxamide.

(b23) “Enopyranuronic acid-based antibiotic fungicides” (FRAC code 23) inhibit the growth of fungi by affecting protein biosynthesis. Examples include blasticidin-S.

(b24) “Hexapyranosyl-based antibiotic fungicides” (FRAC code 24) inhibit fungal growth by affecting protein biosynthesis. Examples include kasugamycin.

(b25) “Glucopyranosyl-based antibiotic fungicides that affect protein synthesis” (FRAC code 25) inhibit fungal growth by affecting protein biosynthesis. Examples include streptomycin.

(b26) “Glucopyranosyl-based antibiotic fungicides that affect trehalase and inositol biosynthesis” (FRAC code 26) inhibit trehalase in the pathway of inositol biosynthesis. Examples include validamycin.

(b27) “Cyanoacetamidoxime-based fungicides (FRAC code 27) include cymoxanil.

(b28) “Carbamate-based fungicides” (FRAC code 28) are considered as fungal growth inhibitors acting on multiple sites. They are believed to inhibit the synthesis of fatty acids in cell membranes, which then disrupts the permeability of the cell membrane. Propamocarb, propamocarb hydrochloride, iodocarb and prothiocarb are examples of this class of fungicides.

(b29) “Fungicides that uncouple oxidative phosphorylation” (FRAC code 29) inhibit the respiration of fungi by uncoupling oxidative phosphorylation. Respiratory inhibition prevents the normal growth and development of fungi. This class includes 2,6-dinitroanilines such as fluazinam, pyrimidonhydrazones such as ferimzone, and dinitrophenyl crotonates such as dinocap, meptyldinocap and binapacryl.

(b30) “Organic Tin Compound Fungicides” (FRAC code 30) inhibit adenosine triphosphate (ATP) synthase in the oxidative phosphorylation pathway. Examples include fentin acetate, fentin chloride and fentin hydroxide.

(b31) “Carboxylic Acid Fungicides” (FRAC code 31) inhibit fungal growth by acting on type II deoxyribonucleic acid (DNA) topoisomerase (gyrase). Examples include oxolinic acid.

(b32) “Heteroatom-based fungicides” (FRAC code 32) are believed to affect the synthesis of DNA / ribonucleic acid (RNA). Heteroaromatic fungicides include isoxazole and isothiazolone fungicides. Isoxazoles include hymexazole, and isothiazolones include octilinone.

(b33) “Phosphonate-based fungicides” (FRAC code 33) phosphorous acid and its various salts, including fosetyl-aluminum.

(b34) “Phthalamic acid-based fungicides” (FRAC code 34) include teclophthalam.

(b35) “Benzotriazine-based fungicides” (FRAC code 35) include triazoxide.

(b36) “Benzene-sulfonamide-based fungicides” (FRAC code 36) include fluusulfamide.

(b37) “Pyridazinone-based fungicides” (Fungicide Resistance Prevention Committee (FRAC) Code 37) include diclomesine.

(b38) “Thiophene-carboxamide-based fungicides” (FRAC code 38) are believed to interfere with ATP formation. Examples include silthiofam.

(b39) “Pyrimidinamide-based fungicides” (FRAC code 39) inhibit the growth of fungi by affecting the biosynthesis of phospholipids and include diflumetorim.

(b40) “Carboxylic acid amide-based fungicides (CAA)” (FRAC code 40) are believed to inhibit phospholipid biosynthesis and cell wall formation. Inhibition of these processes inhibits growth and leads to the death of the target fungus. Carboxylic acid amide fungicides include cinnamic acid amide fungicides, valine carbamate fungicides and mandelic amide fungicides. Cinnamic acid amides include dimethomorph and flumorph. Valinamide carbamates include bentiavalicarb, bentiavalicarb-isopropyl, iprivalicarb and valifenalate (valifenal). Mandelic acid amides include mandipropamide, N - [2- [4 - [[3- (4-chlorophenyl) -2-propin-1-yl] oxy] -3-methoxyphenyl] ethyl] -3-methyl-2 - [( methylsulfonyl) amino] butanamide and N - [2- [4 - [[3- (4-chlorophenyl) -2-propin-1-yl] oxy] -3-methoxyphenyl] ethyl] -3-methyl-2 - [( ethylsulfonyl) amino] butanamide.

(b41) “Tetracycline-based antibiotic fungicides” (FRAC code 41) inhibit fungal growth by attacking nicotinamide adenine dinucleotide (NADH) oxidoreductase complex 1. Examples include oxytetracycline.

(b42) “Thiocarbamate-based fungicides (b42)” (FRAC code 42) include metasulfocarb.

(b43) “Benzamide-based fungicides” (FRAC code 43) inhibit fungal growth by delocalizing spectrin-like proteins. Examples include acyl picolide fungicides such as fluopicolide and fluopyram.

(b44) “Fungicides inducing the protection of the host plant” (FRAC code P) induce the protective mechanisms of the host plant. Fungicides for inducing protection of the host plant include benzo-thiadiazole, benzisothiazole and thiadiazole-carboxamide fungicides. Benzo-thiadiazoles include acibenzolar- S- methyl. Benzisothiazoles include probenazole. Thiadiazole-carboxamides include thiadinyl and isothianyl.

(b45) “Fungicides with contact activity acting on multiple sites” inhibit the growth of fungi through multiple sites of application of action and have contact / prophylactic activity. This class of fungicides includes: (b45.1) “copper-based fungicides” (FRAC code M1) ”, (b45.2)“ sulfur-based fungicides ”(FRAC code M2), (b45.3)“ dithiocarbamate fungicides ”( FRAC code M3), (b45.4) “phthalimide fungicides” (FRAC code M4), (b45.5) “chloronitrile fungicides” (FRAC code M5), (b45.6) “sulfamide-based fungicides” (FRAC code M6 ), (b45.7) “guanidine-based fungicides” (FRAC code M7), (b45.8) “triazine fungicides” (FRAC code M8) and (b45.9) “quinone fungicides” (FRAC code M9). “Copper-based fungicides” are inorganic compounds containing copper, usually in the oxidized state of copper (II); examples include copper oxychloride, copper sulfate and copper hydroxide, including compositions such as Bordeaux mixture (tribasic copper sulfate). “Sulfur-based fungicides” are inorganic chemicals containing rings or chains of sulfur atoms; examples include elemental sulfur. “Dithiocarbamate fungicides” contain a fragment of a dithiocarbamate molecule; examples include mancozeb, metira, propineb, ferbam, maneb, thiram, kineb, and tsir. “Phthalimide fungicides” contain a fragment of a phthalimide molecule; examples include folpet, captan and captafol. “Chloronitrile fungicides” contain a chlorine and cyano substituted aromatic ring; examples include chlorothalonil. “Sulfamide-based fungicides” include dichlorofluanide and tolylfluanide. “Guanidine-based fungicides” include dodine, guazatin, and imoctadine, including iminoctadine albesylate and iminoctadine triacetate. “Triazine fungicides” include anilazine. “Quinone fungicides” include dithianone.

(b46) “Other fungicides than fungicides of classes (b1) to (b45)” include certain fungicides whose mechanism of action may not be known. These include: (b46.1) “thiazole carboxamide fungicides” (FRAC code U5), (b46.2) “phenylacetamide fungicides” (FRAC code U6), (b46.3) “quinazoline fungicides” (FRAC code U7) and (b46 .4) “benzophenone fungicides” (FRAC code U8). Thiazolecarboxamides include ethaboxam. Phenylacetamides include cyclofenamide and N - [[(cyclopropylmethoxy) amino] [6- (difluoromethoxy) -2,3-difluorophenyl] methylene] benzeneacetamide. Quinazolinones include proquinazide and 2-butoxy-6-iodo-3-propyl-4 H -1-benzopyran-4-one. Benzophenones include metraphenone and pyriophenone. Class (b46) also includes betoxazine, neo-azosine (iron methanarsonate), fenpirazamine, pyrronitrin, quinomethionate, tebufloquin, N - [2- [4 - [[3- (4-chlorophenyl) -2-propin-1-yl] hydroxy] -3-methoxyphenyl] ethyl] -3-methyl-2 - [(methylsulfonyl) amino] butanamide, N - [2- [4 - [[3- (4-chlorophenyl) -2-propin-1-yl] hydroxy] -3-methoxyphenyl] ethyl] -3-methyl-2 - [(ethylsulfonyl) amino] butanamide, 2 - [[2-fluoro-5- (trifluoromethyl) phenyl] thio] -2- [3- (2- methoxyphenyl) -2-thiazolidinylidene] acetonitrile, 3- [5- (4-chlorophenyl) -2,3-dimethyl-3-isoxazolidinyl] pyridine, 4-fluorophenyl N - [1 - [[[1- (4-cyanophenyl) ethyl] sulfonyl] methyl] propyl] carbamate, 5-chloro-6- (2,4,6-trifluoro enyl) -7- (4-methylpiperidin-1-yl) [1,2,4] triazolo [1,5- a] pyrimidine, N - (4-chloro-2-nitrophenyl) - N -ethyl-4-methylbenzenesulfonamide , N - [[(cyclopropylmethoxy) amino] [6- (difluoromethoxy) -2,3-difluorophenyl] methylene] benzeneacetamide, N '- [4- [4-chloro-3- (trifluoromethyl) phenoxy] -2,5- dimethylphenyl] - N- ethyl- N- methylmethanimidamide and 1 - [(2-propenylthio) carbonyl] -2- (1-methyleneethyl) -4- (2-methylphenyl) -5-amino-1 H -pyrazol-3-one .

Thus, it should be noted a mixture (i.e., a composition) containing as component (a) a solid form of compound 1 and as component (b) at least one fungicidal compound selected from the group consisting of the classes described above (b1 ) - (b46). It should also be noted options for implementation, where component (b) includes at least one fungicide from each of two different groups selected from (b1) to (b46). It should also be noted a composition containing the specified mixture (in a fungicidally effective amount) and additionally containing at least one additional component selected from the group consisting of surfactants, solid diluents and liquid diluents. Of particular note is a mixture (i.e., a composition) containing a solid form of compound 1 and at least one fungicidal compound selected from the group of specific compounds listed above in connection with classes (b1) to (b46). Of particular note is a composition containing said mixture (in a fungicidally effective amount) and further comprising at least one additional surfactant selected from the group consisting of surfactants, solid diluents and liquid diluents.

Examples of other biologically active compounds or agents with which the compounds of the present invention can be formulated are insecticides such as: abamectin, acephate, acetamipride, acetoprol, aldicarb, amidoflumet (S-1955), amitraz, avermectin, azadirachtin, azinphos-methyl, bifentrin , biphenazate, bistrifluuron, buprofesin, carbofuran, kartap, chloromethionate, chlorfenapyr, chlorfluazuron, chlorantraniliprol (DPX-E2Y45), chlorpyrifos, chlorpyrifos-methyl, chlorobenzylate, chromafenoside, 3-chlorothirolidin-3-cyanophenidine -pyridinyl) - N - [4-cyano-2-m ethyl-6 - [(methylamino) carbonyl] phenyl] -1 H -pyrazole-5-carboxamide), cyflumetophen, cyfluthrin, beta-cyfluthrin, cygalotrin, gamma-cygalotrin, lambda-cygalotrin, cyhexatin, cypermethrin, cyromazine, deltamethurin, diafentaf , diazinon, dicofol, dieldrin, dienohlor, diflubenzuron, dimeflutrin, dimethoate, dinotefuran, diofenolan, emamectin, endosulfan, esfenvalerate, ethiprole, etoxazole, fenamiphos, fenazaquin, fenbutalinoksid, fenothiocarb, fenoxycarb, fenpropathrin, fenpyroximate, fenvalerate, fipronil, flonicamid, flubendiamide flucytrinate, tau fluvalinate , flufenerim (UR-50701), flufenoxuron, phonophos, halofenoside, hexaflumuron, hexithiazox, hydramethylnone, imitsiafos, imidacloprid, indoxacarb, isofenfos, methenfiloxidone, metafloroformidometh, methaflorofoxidomethone, metafloumofidoformidone, metafloumofidoformidone, metaflouformidone monocrotophos, nitenpyram, nithiazine, novaluron (XDE-007), noviflumuron, oxamyl, parathion, parathion-methyl, permethrin, forat, fosalon, fosmet, phosphamidone, pyrimicarb, profenofos, proflutrin, propargyt, prothiropyrbin pyrrithirobutyr, pyrrithiropyrbene pyrrithirobutyrpiripyrbutyrbirpirbiparbithiropyrbin pyrrithirobutyrpirypirbirbiparbithiropyrbin pyrrithirobutyr pyrid bin, pyridalyl, pirifluhinazon, pyriprole, pyriproxyfen, rotenone, ryanodine, spinetoram, spinosad, spirodiclofen, spiromesifen (BSN 2060), spirotetramat, sulprofos, tebufenozide, tebufenpyrad, teflubenzuron, tefluthrin, terbufos, tetrachlorvinphos, thiacloprid, thiamethoxam, thiodicarb, tiosultap- sodium, tolfenpyrad, tralomethrin, triazamate, trichlorfon and triflumuron.

Further examples of insecticides which can be a compound of the present invention include acequinocyl, acrinathrin, afidopiropen, benfuracarb, bensultap, borate, kaduzafos, carbaryl, karzol, clofentezine, tsiklaniliprol, cycloprothrin, tsikloksaprid, cypermethrin, alpha-cypermethrin, zeta-cypermethrin, dimegifo , etofenprox, fenitrotion, flomethoquine, flufenoxystrobin, flupiprol, flupiradifuron, fluvalinate, tau fluvalinate, formanat, fostiazat, heptaflutrin, insecticidal soaps, meperflutrin, methiodicarb, monoftor, monoftor in, pythlubumide, pyriminostrobin, silafluofen, spirodiclofen, sulfoxaflor, tetramethrin, tetramethylflutrin, triflomesopyrim and the internal salt 1 - [(2-chloro-5-thiazolyl) methyl] -3- (3,5-diclophenyl) -2-hydroxy-9 -methyl-4-oxo-4 H -pyrido [1,2- a] pyrimidine.

Examples of other biologically active compounds or agents with which the compounds of the present invention can be formulated are nematicides, such as aldicarb, imiciafos, oxamyl and phenamiphos. Further examples of nematicides with which the compounds of the present invention can be formulated are abamectin, caduzafos, carbofuran, chloropicrin, dazometh, 1,3-dichloropropene, dimethyl sulfide, etoprofos, phenamiphos, flufensulfone, fluopyram, fostiazate, imitsiafos metipodium, iprodion ), spiro tetramate, terboufos, thiodicarb, thioxazafen and 8-chloro- N - [(2-chloro-5-methoxyphenyl) sulfonyl] -6- (trifluoromethyl) imidazole [1,2- a ] pyridin-2-caboxamide.

Examples of other biologically active compounds or agents with which the compounds of the present invention can be formulated are bactericides such as streptomycin; and acaricides, such as amitraz, quinomethionate, chlorobenzylate, cienopyrafen, cyhexatin, dicofol, dienochlor, ethoxazole, phenazaquin, fenbutatin oxide, fenpropatrin, fenpiroximate, hexithiazox, proparbit, pyridiaphene and tuber.

Examples of other biological agents with which the compounds of the present invention can be formulated are entomopathogenic bacteria such as Bacillus thuringiens is a subspecies of aizawai , Bacillus thuringiensis of the subspecies kurstaki and encapsulated delta-endotoxins of Bacillus thuringiensis (for example, Cellcap, MPV, MPVII); root bacteria, such as Bacillus firmus ; parasitic nematode bacteria such as Pasteuria nishizawae ; entomopathogenic fungi, such as green stone fungus; and an entomopathogenic virus (both naturally occurring and genetically modified), such as baculovirus, nucleopolyhedrovirus (NPV), such as Helicoverp zea nucleopolyhedrovirus (HzNPV), Anagrapha falcifera nucleopolyhedrovirus (AfNPV); and granulosis virus (GV), such as Cydia pomonella granulosis virus (CpGV).

Common references to agricultural remedies (i.e. insecticides, fungicides, nematicides, acaricides, herbicides and biologicals) include The Pesticide Manual, 13th Edition , CDS Tomlin, Ed., British Crop Protection Council, Farnham, Surrey , UK, 2003; and The BioPesticide Manual , 2nd Edition , LG Copping, Ed., British Crop Protection Council, Farnham, Surrey, UK, 2001.

For embodiments where one or more of the data of different mixing participants are applied, the weight ratio of the data of the various mixing participants (in total) and the solid form of compound 1 is typically from about 1: 3000 to about 3000: 1. It should be noted weight ratios from about 1: 300 to about 300: 1 (for example, ratios from about 1:30 to about 30: 1). One of ordinary skill in the art can easily determine the biologically effective amounts of active ingredients required for the desired spectrum of biological activity by simply conducting experiments. It will be obvious that the inclusion of such additional components can expand the spectrum of fungal diseases that are controlled, compared with the spectrum that is controlled using the solid form of compound 1 separately.

Table A below shows embodiments of specific compositions containing a solid form of compound 1 (polymorphic form B) and an additional fungicide.

Table a Component (b) Typical
weight ratio More typical
weight ratio Most typical
weight ratio Illustrative Weight Ratio Acibenzolar- S- methyl from 2: 1 to 1: 180 from 1: 1 to 1:60 from 1: 1 to 1:18 1: 4 Aldimorph from 30: 1 to 1: 3 from 10: 1 to 1: 1 from 7: 1 to 1: 1 3: 1 Amectradine 9: 1 to 1:18 from 3: 1 to 1: 6 from 3: 1 to 1: 3 1: 1 Amisulbrom 6: 1 to 1:18 from 2: 1 to 1: 6 from 1: 1 to 1: 6 1: 2 Anilazine 90: 1 to 2: 1 30: 1 to 4: 1 from 22: 1 to 4: 1 8: 1 Azaconazole from 7: 1 to 1:18 from 2: 1 to 1: 6 from 2: 1 to 1: 4 1: 2 Azoxystrobin 9: 1 to 1:12 from 3: 1 to 1: 4 from 3: 1 to 1: 3 1: 1 Benalaxil 4: 1 to 1:18 from 1: 1 to 1: 6 from 1: 1 to 1: 6 1: 2 Benalaxyl-M 4: 1 to 1:36 from 1: 1 to 1:12 from 1: 1 to 1: 8 1: 3 Benodanil from 18: 1 to 1: 6 from 6: 1 to 1: 2 from 4: 1 to 1: 2 2: 1 Benomil from 45: 1 to 1: 4 from 15: 1 to 1: 1 from 11: 1 to 1: 1 4: 1 Bentiavalicarb or bentiavalicarb-isopropyl from 2: 1 to 1:36 from 1: 1 to 1:12 from 1: 1 to 1:12 1: 4 Betoxazine 150: 1 to 1:36 50: 1 to 1:12 from 15: 1 to 2: 1 5: 1 Binapacryl 150: 1 to 1:36 50: 1 to 1:12 from 15: 1 to 2: 1 5: 1 Biphenyl 150: 1 to 1:36 50: 1 to 1:12 from 15: 1 to 2: 1 5: 1 Bitertanol from 15: 1 to 1: 5 from 5: 1 to 1: 2 from 3: 1 to 1: 2 1: 1

Bixafen from 12: 1 to 1: 9 from 4: 1 to 1: 3 from 2: 1 to 1: 3 1: 1 Blasticidin-S 3: 1 to 1:90 from 1: 1 to 1:30 from 1: 4 to 1:30 1:12 Boscalid from 18: 1 to 1: 6 from 6: 1 to 1: 2 from 4: 1 to 1: 2 2: 1 Bromukonazole from 15: 1 to 1: 9 from 5: 1 to 1: 3 from 3: 1 to 1: 3 1: 1 Bupirimat 3: 1 to 1:90 from 1: 1 to 1:30 from 1: 3 to 1:30 1:10 Captafol from 90: 1 to 1: 4 from 30: 1 to 1: 2 from 15: 1 to 2: 1 5: 1 Captan from 90: 1 to 1: 4 from 30: 1 to 1: 2 from 15: 1 to 2: 1 5: 1 Carbendazim from 45: 1 to 1: 4 from 15: 1 to 1: 2 11: 1 to 2: 1 4: 1 Carboxin from 18: 1 to 1: 6 from 6: 1 to 1: 2 from 4: 1 to 1: 2 2: 1 Carpropamide from 15: 1 to 1: 9 from 5: 1 to 1: 3 from 3: 1 to 1: 3 1: 1 Chloroneb from 300: 1 to 2: 1 from 100: 1 to 4: 1 from 100: 1 to 14: 1 35: 1 Chlorothalonil from 90: 1 to 1: 4 from 30: 1 to 1: 2 from 15: 1 to 2: 1 5: 1 Chlozolinate from 45: 1 to 1: 2 from 15: 1 to 2: 1 11: 1 to 2: 1 4: 1 Clotrimazole from 15: 1 to 1: 9 from 5: 1 to 1: 3 from 3: 1 to 1: 3 1: 1 Copper salts such as Bordeaux mixture (tribasic copper sulfate), copper oxychloride, copper sulfate and copper hydroxide 450: 1 to 1: 1 from 150: 1 to 4: 1 45: 1 to 5: 1 15: 1 Cyazofamide 4: 1 to 1:18 from 1: 1 to 1: 6 from 1: 1 to 1: 6 1: 2 Tsiflufenamid from 1: 1 to 1:90 from 1: 2 to 1:30 from 1: 2 to 1:24 1: 6 Cymoxanil 6: 1 to 1:18 from 2: 1 to 1: 6 from 1: 1 to 1: 5 1: 2

Cyproconazole 4: 1 to 1:18 from 1: 1 to 1: 6 from 1: 1 to 1: 6 1: 2 Cyprodinil from 22: 1 to 1: 9 from 7: 1 to 1: 3 from 4: 1 to 1: 2 2: 1 Dichlorofluanide 150: 1 to 1:36 50: 1 to 1:12 from 15: 1 to 2: 1 5: 1 Diclocimet 150: 1 to 1:36 50: 1 to 1:12 from 15: 1 to 2: 1 5: 1 Diclomesine from 15: 1 to 1: 9 from 5: 1 to 1: 3 from 3: 1 to 1: 3 1: 1 Dicloran 150: 1 to 1:36 50: 1 to 1:12 from 15: 1 to 2: 1 5: 1 Dietofencarb from 22: 1 to 1: 9 from 7: 1 to 1: 3 from 7: 1 to 1: 2 2: 1 Diphenoconazole 4: 1 to 1:36 from 1: 1 to 1:12 from 1: 1 to 1:12 1: 3 Diflumetor 150: 1 to 1:36 50: 1 to 1:12 from 15: 1 to 2: 1 5: 1 Dimethyrimol 3: 1 to 1:90 from 1: 1 to 1:30 from 1: 3 to 1:30 1: 8 Dimetomorph from 9: 1 to 1: 6 from 3: 1 to 1: 2 from 3: 1 to 1: 2 1: 1 Dimoxystrobin 9: 1 to 1:18 from 3: 1 to 1: 6 from 2: 1 to 1: 4 1: 1 Diniconazole 3: 1 to 1:36 from 1: 1 to 1:12 from 1: 1 to 1: 8 1: 3 Diniconazole-M 3: 1 to 1:90 from 1: 1 to 1:30 from 1: 1 to 1:12 1: 3 Dinocap from 7: 1 to 1: 9 from 2: 1 to 1: 3 from 2: 1 to 1: 3 1: 1 Dithianon from 15: 1 to 1: 4 from 5: 1 to 1: 2 from 5: 1 to 1: 2 2: 1 Dodemorph from 30: 1 to 1: 3 from 10: 1 to 1: 1 from 7: 1 to 1: 1 3: 1 Dodin from 30: 1 to 1: 2 from 10: 1 to 2: 1 from 10: 1 to 2: 1 4: 1 Edifenfos from 30: 1 to 1: 9 from 10: 1 to 1: 3 from 3: 1 to 1: 3 1: 1 Enoxastrobin 9: 1 to 1:18 from 3: 1 to 1: 6 from 2: 1 to 1: 4 1: 1 Epoxiconazole 3: 1 to 1:36 from 1: 1 to 1:12 from 1: 1 to 1: 7 1: 3

Ethaconazole 3: 1 to 1:36 from 1: 1 to 1:12 from 1: 1 to 1: 7 1: 3 Etaboxam from 7: 1 to 1: 9 from 2: 1 to 1: 3 from 2: 1 to 1: 3 1: 1 Etirimol from 30: 1 to 1: 3 from 10: 1 to 1: 1 from 7: 1 to 1: 1 3: 1 Etridiazole from 30: 1 to 1: 9 from 10: 1 to 1: 3 from 7: 1 to 1: 2 2: 1 Famoxadone 9: 1 to 1:18 from 3: 1 to 1: 6 from 2: 1 to 1: 4 1: 1 Fenamidone 6: 1 to 1:18 from 2: 1 to 1: 6 from 2: 1 to 1: 4 1: 1 Fenarimol 3: 1 to 1:90 from 1: 1 to 1:30 from 1: 2 to 1:24 1: 7 Fenbuconazole from 3: 1 to 1:30 from 1: 1 to 1:10 from 1: 1 to 1:10 1: 3 Fenfuram from 18: 1 to 1: 6 from 6: 1 to 1: 2 from 4: 1 to 1: 2 1: 1 Phenhexamide from 30: 1 to 1: 2 from 10: 1 to 2: 1 from 10: 1 to 2: 1 4: 1 Phenoxanil 150: 1 to 1:36 50: 1 to 1:12 from 15: 1 to 1: 1 4: 1 Fenpiclonil from 75: 1 to 1: 9 from 25: 1 to 1: 3 from 15: 1 to 2: 1 5: 1 Fenpropidine from 30: 1 to 1: 3 from 10: 1 to 1: 1 from 7: 1 to 1: 1 2: 1 Fenpropimorph from 30: 1 to 1: 3 from 10: 1 to 1: 1 from 7: 1 to 1: 1 2: 1 Fenpirazamine from 100: 1 to 1: 100 10: 1 to 1:10 from 3: 1 to 1: 3 1: 1 Fentin salt, e.g. acetate, chloride or hydroxide from 15: 1 to 1: 9 from 5: 1 to 1: 3 from 3: 1 to 1: 3 1: 1 Ferbam from 300: 1 to 1: 2 from 100: 1 to 2: 1 30: 1 to 4: 1 10: 1 Ferimson from 30: 1 to 1: 5 from 10: 1 to 1: 2 from 7: 1 to 1: 2 2: 1 Fluazinam from 22: 1 to 1: 5 from 7: 1 to 1: 2 from 3: 1 to 1: 2 1: 1 Fludioxonil from 7: 1 to 1:12 from 2: 1 to 1: 4 from 2: 1 to 1: 4 1: 1 Flumeover from 9: 1 to 1: 6 from 3: 1 to 1: 2 from 3: 1 to 1: 2 1: 1 Flumorf 9: 1 to 1:18 from 3: 1 to 1: 6 from 3: 1 to 1: 3 1: 1

Fluopicolide 3: 1 to 1:18 from 1: 1 to 1: 6 from 1: 1 to 1: 6 1: 2 Fluopyram from 15: 1 to 1:90 from 5: 1 to 1:30 from 3: 1 to 1: 3 1: 1 Fluoromide from 150: 1 to 2: 1 50: 1 to 4: 1 from 37: 1 to 5: 1 14: 1 Fluoxastrobin 4: 1 to 1:18 from 1: 1 to 1: 6 from 1: 1 to 1: 6 1: 2 Fluquinconazole 4: 1 to 1:12 from 1: 1 to 1: 4 from 1: 1 to 1: 4 1: 2 Fluzilazole from 15: 1 to 1: 9 from 5: 1 to 1: 3 from 3: 1 to 1: 3 1: 1 Flusulfamide from 90: 1 to 1: 2 30: 1 to 2: 1 from 15: 1 to 2: 1 5: 1 Flutianil from 7: 1 to 1:36 from 2: 1 to 1:12 from 1: 1 to 1: 6 1: 2 Flutolanil from 18: 1 to 1: 6 from 6: 1 to 1: 2 from 4: 1 to 1: 2 1: 1 Flutriafol 4: 1 to 1:12 from 1: 1 to 1: 4 from 1: 1 to 1: 4 1: 2 Fluxapiroxade from 12: 1 to 1: 9 from 4: 1 to 1: 3 from 2: 1 to 1: 3 1: 1 Folpet from 90: 1 to 1: 4 from 30: 1 to 1: 2 from 15: 1 to 2: 1 5: 1 Fosetil aluminum 225: 1 to 2: 1 75: 1 to 5: 1 30: 1 to 5: 1 12: 1 Fuberidazole from 45: 1 to 1: 4 from 15: 1 to 1: 2 11: 1 to 2: 1 4: 1 Furalaxil from 15: 1 to 1:45 5: 1 to 1:15 from 1: 1 to 1: 6 1: 2 Furametpir 150: 1 to 1:36 50: 1 to 1:12 from 15: 1 to 2: 1 5: 1 Guazatin or iminoctadine 150: 1 to 1:36 50: 1 to 1:12 from 15: 1 to 2: 1 5: 1 Hexaconazole from 15: 1 to 1:36 5: 1 to 1:12 from 1: 1 to 1: 5 1: 2 Hymexazole 225: 1 to 2: 1 75: 1 to 4: 1 75: 1 to 9: 1 25: 1 Imazalil from 7: 1 to 1:18 from 2: 1 to 1: 6 from 1: 1 to 1: 5 1: 2 Imibenconazole from 15: 1 to 1:36 5: 1 to 1:12 from 1: 1 to 1: 5 1: 2 Iodocarb 150: 1 to 1:36 50: 1 to 1:12 from 15: 1 to 2: 1 4: 1

Ipconazole from 15: 1 to 1:36 5: 1 to 1:12 from 1: 1 to 1: 5 1: 2 Iprobenfos 150: 1 to 1:36 50: 1 to 1:12 from 15: 1 to 2: 1 5: 1 Iprodion from 120: 1 to 1: 2 40: 1 to 2: 1 from 15: 1 to 2: 1 5: 1 Iprovalicarb from 9: 1 to 1: 9 from 3: 1 to 1: 3 from 2: 1 to 1: 3 1: 1 Isoprothiolan from 150: 1 to 2: 1 50: 1 to 4: 1 45: 1 to 5: 1 15: 1 Isopyrazam from 12: 1 to 1: 9 from 4: 1 to 1: 3 from 2: 1 to 1: 3 1: 1 Isothianil from 12: 1 to 1: 9 from 4: 1 to 1: 3 from 2: 1 to 1: 3 1: 1 Kasugamycin from 7: 1 to 1:90 from 2: 1 to 1:30 from 1: 2 to 1:24 1: 7 Kresoxim-methyl from 7: 1 to 1:18 from 2: 1 to 1: 6 from 2: 1 to 1: 4 1: 1 Mankozeb from 180: 1 to 1: 3 60: 1 to 2: 1 from 22: 1 to 3: 1 7: 1 Mandipropamide 6: 1 to 1:18 from 2: 1 to 1: 6 from 2: 1 to 1: 4 1: 1 Maneb from 180: 1 to 1: 3 60: 1 to 2: 1 from 22: 1 to 3: 1 7: 1 Mepanipyrim from 18: 1 to 1: 3 from 6: 1 to 1: 1 from 6: 1 to 1: 1 2: 1 Mepronil from 7: 1 to 1:36 from 2: 1 to 1:12 from 1: 1 to 1: 6 1: 2 Meptildinocap from 7: 1 to 1: 9 from 2: 1 to 1: 3 from 2: 1 to 1: 3 1: 1 Metalaxyl from 15: 1 to 1:45 5: 1 to 1:15 from 1: 1 to 1: 6 1: 2 Metalaxyl-M from 7: 1 to 1:90 from 2: 1 to 1:30 from 1: 1 to 1:12 1: 4 Metconazole 3: 1 to 1:18 from 1: 1 to 1: 6 from 1: 1 to 1: 6 1: 2 Metasulfocarb 150: 1 to 1:36 50: 1 to 1:12 from 15: 1 to 1: 1 5: 1 Metiram 150: 1 to 1:36 50: 1 to 1:12 from 15: 1 to 1: 1 5: 1 Metinomostrobin 9: 1 to 1:12 from 3: 1 to 1: 4 from 3: 1 to 1: 3 1: 1 Metrafenone 6: 1 to 1:12 from 2: 1 to 1: 4 from 2: 1 to 1: 4 1: 1

Micobutanil 5: 1 to 1:26 from 1: 1 to 1: 9 from 1: 1 to 1: 8 1: 3 Naftinine 150: 1 to 1:36 50: 1 to 1:12 from 15: 1 to 2: 1 5: 1 Neo-asosine
(iron methanarsonate) 150: 1 to 1:36 50: 1 to 1:12 from 15: 1 to 2: 1 5: 1 Noirimole from 15: 1 to 1: 9 from 5: 1 to 1: 3 from 3: 1 to 1: 3 1: 1 Octilinone 150: 1 to 1:36 50: 1 to 1:12 from 15: 1 to 1: 1 4: 1 Ofuras from 15: 1 to 1:45 5: 1 to 1:15 from 1: 1 to 1: 6 1: 2 Orisastrobin 9: 1 to 1:12 from 3: 1 to 1: 4 from 3: 1 to 1: 3 1: 1 Oxadinyl from 15: 1 to 1:45 5: 1 to 1:15 from 1: 1 to 1: 6 1: 2 Oxolinic acid from 30: 1 to 1: 9 from 10: 1 to 1: 3 from 7: 1 to 1: 2 2: 1 Oxpoconazole from 15: 1 to 1:36 5: 1 to 1:12 from 1: 1 to 1: 5 1: 2 Oxycarboxin from 18: 1 to 1: 6 from 6: 1 to 1: 2 from 4: 1 to 1: 2 1: 1 Oxytetracycline from 15: 1 to 1: 9 from 5: 1 to 1: 3 from 3: 1 to 1: 3 1: 1 Pefurazoate 150: 1 to 1:36 50: 1 to 1:12 from 15: 1 to 2: 1 5: 1 Penconazole from 1: 1 to 1:45 from 1: 2 to 1:15 from 1: 2 to 1:15 1: 6 Pencicuron from 150: 1 to 1: 2 50: 1 to 2: 1 11: 1 to 2: 1 4: 1 Penflufen from 12: 1 to 1: 9 from 4: 1 to 1: 3 from 2: 1 to 1: 3 1: 1 Pentiopyrad from 12: 1 to 1: 9 from 4: 1 to 1: 3 from 2: 1 to 1: 3 1: 1 Phosphorous acid and its salts 150: 1 to 1:36 50: 1 to 1:12 from 15: 1 to 2: 1 6: 1 Phthalide 150: 1 to 1:36 50: 1 to 1:12 from 15: 1 to 2: 1 6: 1 Picoxystrobin from 7: 1 to 1:18 from 2: 1 to 1: 6 from 1: 1 to 1: 5 1: 2 Piperaline from 15: 1 to 1: 9 from 5: 1 to 1: 3 from 3: 1 to 1: 3 1: 1

Polyoxin from 15: 1 to 1: 9 from 5: 1 to 1: 3 from 3: 1 to 1: 3 1: 1 Probenazole from 15: 1 to 1: 9 from 5: 1 to 1: 3 from 3: 1 to 1: 3 1: 1 Cool from 22: 1 to 1: 4 from 7: 1 to 1: 1 from 7: 1 to 1: 2 2: 1 Procymidone from 45: 1 to 1: 3 from 15: 1 to 1: 1 11: 1 to 2: 1 4: 1 Propamocarb or Propamocarb Hydrochloride from 30: 1 to 1: 2 from 10: 1 to 2: 1 from 10: 1 to 2: 1 4: 1 Propiconazole 4: 1 to 1:18 from 1: 1 to 1: 6 from 1: 1 to 1: 5 1: 2 Propineb from 45: 1 to 1: 2 from 15: 1 to 2: 1 11: 1 to 2: 1 4: 1 Proquinazide 3: 1 to 1:36 from 1: 1 to 1:12 from 1: 1 to 1:12 1: 3 Prothiocarb 9: 1 to 1:18 from 3: 1 to 1: 6 from 3: 1 to 1: 3 1: 1 Prothioconazole 6: 1 to 1:18 from 2: 1 to 1: 6 from 1: 1 to 1: 5 1: 2 Pyraclostrobin 9: 1 to 1:18 from 3: 1 to 1: 6 from 2: 1 to 1: 4 1: 1 Pyrimethostrobin 9: 1 to 1:18 from 3: 1 to 1: 6 from 2: 1 to 1: 4 1: 1 Pyraxystrobin 9: 1 to 1:18 from 3: 1 to 1: 6 from 2: 1 to 1: 4 1: 1 Pyrazophos 150: 1 to 1:36 50: 1 to 1:12 from 15: 1 to 1: 1 4: 1 Piribenkarb from 15: 1 to 1: 6 from 5: 1 to 1: 2 from 4: 1 to 1: 2 1: 1 Pyrifenox from 15: 1 to 1: 9 from 5: 1 to 1: 3 from 3: 1 to 1: 3 1: 1 Pyrimethanil from 30: 1 to 1: 6 from 10: 1 to 1: 2 from 3: 1 to 1: 2 1: 1 Pyriophenone 6: 1 to 1:12 from 2: 1 to 1: 4 from 2: 1 to 1: 4 1: 1 Pyroquilone from 15: 1 to 1: 9 from 5: 1 to 1: 3 from 3: 1 to 1: 3 1: 1 Pyrrolnitrin 150: 1 to 1:36 50: 1 to 1:12 from 15: 1 to 2: 1 5: 1 Quinconazole 4: 1 to 1:12 from 1: 1 to 1: 4 from 1: 1 to 1: 4 1: 2

Quinomethionate 150: 1 to 1:36 50: 1 to 1:12 from 15: 1 to 2: 1 5: 1 Quinoxifene 4: 1 to 1:18 from 1: 1 to 1: 6 from 1: 1 to 1: 6 1: 2 Quintozen 150: 1 to 1:36 50: 1 to 1:12 from 15: 1 to 2: 1 5: 1 Silthiofam from 7: 1 to 1:18 from 2: 1 to 1: 6 from 2: 1 to 1: 4 1: 1 Simeconazole from 15: 1 to 1:36 5: 1 to 1:12 from 1: 1 to 1: 5 1: 2 Spiroxamine from 22: 1 to 1: 4 from 7: 1 to 1: 2 from 5: 1 to 1: 2 2: 1 Streptomycin from 15: 1 to 1: 9 from 5: 1 to 1: 3 from 3: 1 to 1: 3 1: 1 Sulfur from 300: 1 to 3: 1 from 100: 1 to 9: 1 75: 1 to 9: 1 25: 1 Tebuconazole from 7: 1 to 1:18 from 2: 1 to 1: 6 from 1: 1 to 1: 5 1: 2 Tebufloquin from 100: 1 to 1: 100 10: 1 to 1:10 from 3: 1 to 1: 3 1: 1 Teclofthalam 150: 1 to 1:36 50: 1 to 1:12 from 15: 1 to 2: 1 5: 1 Teknazen 150: 1 to 1:36 50: 1 to 1:12 from 15: 1 to 2: 1 5: 1 Terbinafine 150: 1 to 1:36 50: 1 to 1:12 from 15: 1 to 2: 1 5: 1 Tetraconazole from 15: 1 to 1:36 5: 1 to 1:12 from 1: 1 to 1: 5 1: 2 Thiabendazole from 45: 1 to 1: 4 from 15: 1 to 1: 2 11: 1 to 2: 1 4: 1 Tiflusamide from 15: 1 to 1: 9 from 5: 1 to 1: 3 from 3: 1 to 1: 3 1: 1 Thiophanate from 45: 1 to 1: 3 from 15: 1 to 2: 1 11: 1 to 2: 1 4: 1 Thiophanate methyl from 45: 1 to 1: 3 from 15: 1 to 2: 1 11: 1 to 2: 1 4: 1 Tiram from 150: 1 to 1: 2 50: 1 to 2: 1 from 37: 1 to 5: 1 14: 1 Thiadinyl from 12: 1 to 1: 9 from 4: 1 to 1: 3 from 2: 1 to 1: 3 1: 1 Tolclofos methyl from 150: 1 to 1: 2 50: 1 to 2: 1 from 37: 1 to 5: 1 14: 1 Tolylfluanide 150: 1 to 1:36 50: 1 to 1:12 from 15: 1 to 2: 1 5: 1

Triadimephone from 15: 1 to 1:36 5: 1 to 1:12 from 1: 1 to 1: 5 1: 2 Triadimenol from 15: 1 to 1:36 5: 1 to 1:12 from 1: 1 to 1: 5 1: 2 Triarimol 3: 1 to 1:90 from 1: 1 to 1:30 from 1: 2 to 1:24 1: 7 Triazoxide 150: 1 to 1:36 50: 1 to 1:12 from 15: 1 to 2: 1 5: 1 Tricyclazole from 15: 1 to 1: 9 from 5: 1 to 1: 3 from 3: 1 to 1: 3 1: 1 Tridemorph from 30: 1 to 1: 3 from 10: 1 to 1: 1 from 7: 1 to 1: 1 2: 1 Trifloxystrobin 6: 1 to 1:18 from 2: 1 to 1: 6 from 2: 1 to 1: 4 1: 1 Triflumisole from 15: 1 to 1: 9 from 5: 1 to 1: 3 from 3: 1 to 1: 3 1: 1 Triforin from 15: 1 to 1: 9 from 5: 1 to 1: 3 from 3: 1 to 1: 3 1: 1 Trimorphamide from 45: 1 to 1: 9 from 15: 1 to 1: 3 from 7: 1 to 1: 2 2: 1 Triticonazole from 15: 1 to 1:36 5: 1 to 1:12 from 1: 1 to 1: 5 1: 2 Uniconazole from 15: 1 to 1:36 5: 1 to 1:12 from 1: 1 to 1: 5 1: 2 Validamycin 150: 1 to 1:36 50: 1 to 1:12 from 3: 1 to 1: 3 1: 1 Valifenalate 6: 1 to 1:18 from 2: 1 to 1: 6 from 2: 1 to 1: 4 1: 1 Winklozolin from 120: 1 to 1: 2 40: 1 to 2: 1 from 15: 1 to 2: 1 6: 1 Tsineb from 150: 1 to 1: 2 50: 1 to 2: 1 from 37: 1 to 5: 1 14: 1 Ciram from 150: 1 to 1: 2 50: 1 to 2: 1 from 37: 1 to 5: 1 14: 1 Zoxamide 6: 1 to 1:18 from 2: 1 to 1: 6 from 2: 1 to 1: 4 1: 1 5-chloro-6- (2,4,6-trifluorophenyl) -7- (4-methylpiperidin-1-yl) [1,2,4] triazolo [1,5-a] pyrimidine from 15: 1 to 1:36 5: 1 to 1:12 from 1: 1 to 1: 6 1: 2

N - [2- [4 - [[3- (4-chlorophenyl) -2-propin-1-yl] oxy] -3-methoxyphenyl] ethyl] -3-methyl-2 - [(methylsulfonyl) amino]
butanamide 6: 1 to 1:18 from 2: 1 to 1: 6 from 2: 1 to 1: 4 1: 1 N - [2- [4 - [[3- (4-chlorophenyl) -2-propin-1-yl] oxy] -3-methoxyphenyl] ethyl] -3-methyl-2 - [(ethylsulfonyl) amino]
butanamide 6: 1 to 1:18 from 2: 1 to 1: 6 from 2: 1 to 1: 4 1: 1 2-Butoxy-6-iodo-3-propyl-4 H -1-benzopyran-4-one 3: 1 to 1:36 from 1: 1 to 1:12 from 1: 1 to 1:12 1: 3 3- [5- (4-Chlorophenyl) -2,3-dimethyl-3-isoxazolidinyl] pyridine from 15: 1 to 1: 9 from 5: 1 to 1: 3 from 3: 1 to 1: 3 1: 1 N '- [4 - [[3 - [(4-chlorophenyl) methyl] -1,2,4-thiadiazol-5-yl] oxy] -2,5-dimethylphenyl] - N -ethyl N -metilmetanimidamid from 20: 1 to 1:20 from 8: 1 to 1: 8 from 3: 1 to 1: 3 1: 1

4-Fluorophenyl- N - [1 - [[[1- (4-cyanophenyl) ethyl] sulfonyl]
methyl] propyl] carbamate 6: 1 to 1:18 from 2: 1 to 1: 6 from 2: 1 to 1: 4 1: 1 N - [[(cyclopropylmethoxy) amino]
[6- (difluoromethoxy) -2,3-difluorophenyl] methylene] benzeneacetamide from 1: 1 to 1:90 from 1: 2 to 1:30 from 1: 2 to 1:24 1: 7 α- [methoxyimino] - N- methyl-2 - [[[1- [3- (trifluoromethyl) phenyl] ethoxy]
imino] methyl] benzeneacetamide 9: 1 to 1:18 from 3: 1 to 1: 6 from 3: 1 to 1: 3 1: 1 N '- [4- [4-chloro-3- (trifluoromethyl) phenoxy] -2,5-dimethylphenyl] - N -ethyl N -metilmetanimidamid from 15: 1 to 1:18 from 5: 1 to 1: 6 from 3: 1 to 1: 3 1: 1 N - (4-chloro-2-nitrophenyl) - N- ethyl-4-methylbenzenesulfonamide from 15: 1 to 1:18 from 5: 1 to 1: 6 from 3: 1 to 1: 3 1: 1 2 - [[[3- (2,6-dichlorophenyl) -1-methyl-2-propen-1-ylidene] amino] oxy] methyl] -α- (methoxyimino) N- methylbenzeneacetamide 9: 1 to 1:18 from 3: 1 to 1: 6 from 3: 1 to 1: 3 1: 1

Pentyl- N - [4 - [[[[(1-methyl-1 H- tetrazol-5-yl) phenylmethylene] amino] oxy]
methyl] -2-thiazolyl] carbamate 9: 1 to 1:18 from 3: 1 to 1: 6 from 3: 1 to 1: 3 1: 1 2 - [(3-Bromo-6-quinolinyl) oxy] - N - (1,1-dimethyl-2-butyn-1-yl) -2- (methylthio) acetamide 5: 1 to 1:22 from 2: 1 to 1: 8 from 2: 1 to 1: 4 1: 1 2 - [(3-Ethinyl-6-quinolinyl) oxy] - N - [1- (hydroxymethyl) -1-methyl-2-propin-1-yl] -2- (methylthio) acetamide 5: 1 to 1:22 from 2: 1 to 1: 8 from 2: 1 to 1: 4 1: 1 N - (1,1-dimethyl-2-butyn-1-yl) -2 - [(3-ethynyl-6-quinolinyl) oxy] -2- (methylthio) acetamide 5: 1 to 1:22 from 2: 1 to 1: 8 from 2: 1 to 1: 4 1: 1 1- [4- [4- [5- (2,6-difluorophenyl) -4,5-dihydro-3-isoxazolyl] -2-thiazolyl] -1-piperidinyl] -2- [5-methyl-3- ( trifluoromethyl) -1 H -pyrazol-1-yl] ethanone from 1: 1 to 1:90 from 1: 2 to 1:30 from 1: 2 to 1:18 1: 6

1- [4- [4- [5 R - (2,6-difluorophenyl) -4,5-dihydro-3-isoxazolyl] -2-thiazolyl] -1-piperidinyl] -2- [5-methyl-3- (trifluoromethyl) -1 H -pyrazol-1-yl] ethanone from 1: 1 to 1:90 from 1: 2 to 1:30 from 1: 2 to 1:18 1: 6 1- [4- [4- [5 - [(2,6-difluorophenoxy) methyl] -4,5-dihydro-3-isoxazolyl] -2-thiazolyl] -1-piperidinyl-2- [5-methyl-3 - (trifluoromethyl) -1 H -pyrazol-1-yl] ethanone from 1: 1 to 1:90 from 1: 2 to 1:30 from 1: 2 to 1:18 1: 6 (2-chloro-6-fluorophenyl) methyl 2- [1- [2- [3,5-bis (difluoromethyl) -1 H- pyrazol-1-yl] acetyl] -4-piperidinyl l] -4-thiazole carboxylate from 1: 1 to 1:90 from 1: 2 to 1:30 from 1: 2 to 1:18 1: 6 (1 R ) -1,2,3,4-tetrahydro-1-naphthalenyl-2- [1- [2- [3,5-bis (difluoromethyl) -1 H -pyrazol-1-yl] acetyl] -4 -piperidinyl] -4-thiazole carboxylate from 1: 1 to 1:90 from 1: 2 to 1:30 from 1: 2 to 1:18 1: 6

[[4-Methoxy-2 - [[[(3 S , 7 R , 8 R , 9 S ) -9-methyl-8- (2-methyl-1-oxopropoxy) -2,6-dioxo-7- ( phenylmethyl) -1,5-dioxonan-3-yl] amino] carbonyl] -3-pyridinyl] oxy] methyl-2-methylpropanoate from 90: 1 to 1: 4 from 30: 1 to 1: 2 from 15: 1 to 3: 1 7: 1 (3 S , 6 S , 7 R , 8 R ) -3 - [[[3- (acetyloxy) -4-methoxy-2-pyridinyl] carbonyl] amino] -6-methyl-4,9-dioxo-8- (phenylmethyl) -1,5-dioxonan-7-yl-2-methylpropanoate from 90: 1 to 1: 4 from 30: 1 to 1: 2 from 15: 1 to 3: 1 7: 1 (3 S , 6 S , 7 R , 8 R ) -3 - [[[3 - [(acetyloxy) methoxy] -4-methoxy-2-pyridinyl] carbonyl] amino] -6-methyl-4,9-dioxo -8- (phenylmethyl) -1,5-dioxonan-7-yl-2-methylpropanoate from 90: 1 to 1: 4 from 30: 1 to 1: 2 from 15: 1 to 3: 1 7: 1

(3 S , 6 S , 7 R , 8 R ) -3 - [[[4-methoxy-3 - [[(2-methylpropoxy) carbonyl] oxy] -2-pyridinyl] carbonyl] amino] -6-methyl- 4,9-dioxo-8- (phenylmethyl) -1,5-dioxonan-7-yl-2-methylpropanoate from 90: 1 to 1: 4 from 30: 1 to 1: 2 from 15: 1 to 3: 1 7: 1 N - [[3- (1,3-benzodioxol-5-ylmethoxy) -4-methoxy-2-pyridinyl] carbonyl] - O - [2,5-dideoxy-3- O - (2-methyl-1-oxopropyl ) -2- (phenylmethyl) -L-arabinonoyl] -L-serine, (1 → 4 ') - lactone from 90: 1 to 1: 4 from 30: 1 to 1: 2 from 15: 1 to 3: 1 7: 1 5-Fluoro-2 - [(4-methylphenyl) methoxy] -4-pyrimidinamine from 20: 1 to 1:20 from 5: 1 to 1: 5 from 3: 1 to 1: 3 1: 1 5-Fluoro-2 - [(4-fluorophenyl) methoxy] -4-pyrimidinamine from 20: 1 to 1:20 from 5: 1 to 1: 5 from 3: 1 to 1: 3 1: 1

5,8-Difluoro- N - [2- [3-methoxy-4 - [[4- (trifluoromethyl) -2-pyridinyl] oxy] phenyl] ethyl] -4-quinazolinamine 40: 1 to 1:10 from 10: 1 to 1: 3 from 5: 1 to 1: 2 1: 1 Pentyl N - [6 - [[[( Z ) - [(1-methyl-1 H- tetrazol-5-yl) phenylmethylene] amino] hydroxy] methyl] -2-pyridinyl] carbamate 40: 1 to 1:10 from 10: 1 to 1: 3 from 5: 1 to 1: 2 1: 1 1,1-Dimethylethyl- N - [6 - [[[( Z ) - [(1-methyl-1 H- tetrazol-5-yl) phenylmethylene] amino] oxy] methyl] -2-pyridinyl] carbamate 40: 1 to 1:10 from 10: 1 to 1: 3 from 5: 1 to 1: 2 1: 1 3-Butyn-1-yl- N - [6 - [[[( Z ) - [(1-methyl-1 H- tetrazol-5-yl) phenylmethylene] amino] oxy] methyl] -2-pyridinyl] carbamate 40: 1 to 1:10 from 10: 1 to 1: 3 from 5: 1 to 1: 2 1: 1 N - (3 ', 4'-difluoro [1,1'-biphenyl] -2-yl) -3- (trifluoromethyl) -2-pyrazinecarboxamide from 20: 1 to 1:20 from 5: 1 to 1: 5 from 3: 1 to 1: 3 1: 1

N - [2- (2,4-Dichlorophenyl) -2-methoxy-1-methylethyl] -3- (difluoromethyl) -1-methyl-1 H -pyrazole-4-carboxamide from 20: 1 to 1:20 from 5: 1 to 1: 5 from 3: 1 to 1: 3 1: 1 3- (Difluoromethyl) - N - [4-fluoro-2- (1,1,2,3,3,3-hexafluoropropoxy) phenyl] -1-methyl-1 H -pyrazole-4-carboxamide from 20: 1 to 1:20 from 5: 1 to 1: 5 from 3: 1 to 1: 3 1: 1 3- (Difluoromethyl) -1-methyl-N- [2- (1,1,2,2-tetrafluoroethoxy) phenyl] -1H-pyrazole-4-carboxamide from 20: 1 to 1:20 from 5: 1 to 1: 5 from 3: 1 to 1: 3 1: 1 Isofetamide from 20: 1 to 1:20 from 5: 1 to 1: 5 from 3: 1 to 1: 3 1: 1 Tolprocarb from 20: 1 to 1:20 from 5: 1 to 1: 5 from 3: 1 to 1: 3 1: 1 (αR) -2 - [(2,5-dimethylphenoxy) methyl] -α-methoxy-N-methylbenzeneacetamide from 20: 1 to 1:20 from 5: 1 to 1: 5 from 3: 1 to 1: 3 1: 1 2,6-Dimethyl-1H, 5H- [1,4] dithiino [2,3-c: 5,6-c '] dipyrrole-1,3,5,7 (2H, 6H) -tetron from 1: 1 to 1: 400 from 1: 4 to 1: 100 from 1: 8 to 1:50 1: 1

1 - [[(2 S , 3 R ) -3- (2-chlorophenyl) -2- (2,4-difluorophenyl) -2-oxiranyl] methyl] -1 H -1,2,4-triazole 36: 1 to 1:30 12: 1 to 1:10 from 6: 1 to 1: 4 1: 1 2 - [[(2 S , 3 R ) -3- (2-chlorophenyl) -2- (2,4-difluorophenyl) -2-oxiranyl] methyl] -1,2-dihydro-3 H -1,2, 4-triazole-3-thion 36: 1 to 1:30 12: 1 to 1:10 from 6: 1 to 1: 4 1: 1 1 - [[(2 S , 3 R ) -3- (2-chlorophenyl) -2- (2,4-difluorophenyl) -2-oxiranyl] methyl] -5- (2-propen-1-ylthio) -1 H -1,2,4-triazole 36: 1 to 1:30 12: 1 to 1:10 from 6: 1 to 1: 4 1: 1 α- [3- (4-chloro-2-fluorophenyl) -5- (2,4-difluorophenyl) -4-isoxazolyl] -3-pyridinomethanol 36: 1 to 1:30 12: 1 to 1:10 from 6: 1 to 1: 4 1: 1 (α S ) - [3- (4-chloro-2-fluorophenyl) -5- (2,4-difluorophenyl) -4-isoxazolyl] -3-pyridinomethanol 36: 1 to 1:30 12: 1 to 1:10 from 6: 1 to 1: 4 1: 1 (α R ) - [3- (4-chloro-2-fluorophenyl) -5- (2,4-difluorophenyl) -4-isoxazolyl] -3-pyridinomethanol 36: 1 to 1:30 12: 1 to 1:10 from 6: 1 to 1: 4 1: 1

3- [2- [3- (4-Chloro-2-fluorophenyl) -5- (2,4-difluorophenyl) -4-isoxazolyl] -2-oxiranyl] pyridine 36: 1 to 1:30 12: 1 to 1:10 from 6: 1 to 1: 4 1: 1 2-Ethyl-3,7-dimethyl-6- [4- (trifluoromethoxy) phenoxy] -4-quinolinylmethyl carbonate 36: 1 to 1:30 12: 1 to 1:10 from 6: 1 to 1: 4 1: 1 α- [2-chloro-4- (4-chlorophenoxy) phenyl] -α-ethyl-1H-1,2,4-triazole-1-ethanol 36: 1 to 1:30 12: 1 to 1:10 from 6: 1 to 1: 4 1: 1 α- [2-chloro-4- (4-chlorophenoxy) phenyl] -α- (1 H -1,2,4-triazol-1-ylmethyl) -1 H -1,2,4-triazol-1-ethanol 36: 1 to 1:30 12: 1 to 1:10 from 6: 1 to 1: 4 1: 1 N- cyclopropyl-3- (difluoromethyl) -5-fluoro-1-methyl- N - [[(2- (1-methylethyl) phenyl] methyl] -1 H- pyrazole-4-carboxamide from 20: 1 to 1:20 from 5: 1 to 1: 5 from 3: 1 to 1: 3 1: 1

N - [[5-chloro-2- (trifluoromethyl) phenyl] methyl] - N- cyclopropyl-3- (difluoromethyl) -5-fluoro-1 - methyl-1 H -pyrazole-4-carboxamide from 20: 1 to 1:20 from 5: 1 to 1: 5 from 3: 1 to 1: 3 1: 1 N - [[2-chloro-6- (trifluoromethyl) phenyl] methyl] - N- cyclopropyl-3- (difluoromethyl) -5-fluoro-1-methyl-1 H -pyrazole-4-carboxamide from 20: 1 to 1:20 from 5: 1 to 1: 5 from 3: 1 to 1: 3 1: 1 N - [[3-chloro-2-fluoro-6- (trifluoromethyl) phenyl] methyl] - N- cyclopropyl-3- (difluoromethyl) -5-fluoro-1-methyl-1 H -pyrazole-4-carboxamide from 20: 1 to 1:20 from 5: 1 to 1: 5 from 3: 1 to 1: 3 1: 1 N- cyclopropyl-3- (difluoromethyl) -5-fluoro-1-methyl- N - [[5-methyl-2- (trifluoromethyl) phenyl] methyl] -1 H- pyrazole-4-carboxamide from 20: 1 to 1:20 from 5: 1 to 1: 5 from 3: 1 to 1: 3 1: 1

N - [[5-chloro-2- (1-methylethyl) phenyl] methyl] - N- cyclopropyl-3- (difluoromethyl) -5-fluoro-1-methyl-1 H -pyrazole-4-carboxamide from 20: 1 to 1:20 from 5: 1 to 1: 5 from 3: 1 to 1: 3 1: 1 N -cyclopropyl- N - [(2-cyclopropylphenyl) methyl] -3- (difluoromethyl) -5-fluoro-1-methyl-1 H -pyrazole-4-carboxamide from 20: 1 to 1:20 from 5: 1 to 1: 5 from 3: 1 to 1: 3 1: 1 N- cyclopropyl-3- (difluoromethyl) - N - [(2-ethyl-4,5-dimethylphenyl) methyl] -5-fluoro-1-methyl-1 H -pyrazole-4-carboxamide from 20: 1 to 1:20 from 5: 1 to 1: 5 from 3: 1 to 1: 3 1: 1 N- cyclopropyl-3- (difluoromethyl) -5-fluoro- N - [[5-fluoro-2- (1-methylethyl) phenyl] methyl-1-methyl-1 H -pyrazole-4-carboxamide from 20: 1 to 1:20 from 5: 1 to 1: 5 from 3: 1 to 1: 3 1: 1

The 1,1-dimethylethyl at position 2 is (b6j) N -cyclopropyl-3- (difluoromethyl) - N - [[2- (1,1-dimethylethyl) phenyl] methyl] -5-fluoro-1-methyl-1 H- pyrazole-4-carboxamide from 20: 1 to 1:20 from 5: 1 to 1: 5 from 3: 1 to 1: 3 1: 1 N-cyclopropyl-3- (difluoromethyl) -N - [(2-ethyl-5-fluorophenyl) methyl] -5-fluoro-1-methyl-1H-pyrazole-4-carboxamide from 20: 1 to 1:20 from 5: 1 to 1: 5 from 3: 1 to 1: 3 1: 1 N -cyclopropyl- N - [(2-cyclopropyl-5-fluorophenyl) methyl] -3- (difluoromethyl) -5-fluoro-1-methyl-1 H -pyrazole-4-carboxamide from 20: 1 to 1:20 from 5: 1 to 1: 5 from 3: 1 to 1: 3 1: 1 N - [(5-chloro-2-ethylphenyl) methyl] - N- cyclopropyl-3- (difluoromethyl) -5-fluoro-1-methyl-1 H -pyrazole-4-carboxamide from 20: 1 to 1:20 from 5: 1 to 1: 5 from 3: 1 to 1: 3 1: 1

N-cyclopropyl-3- (difluoromethyl) -5-fluoro-N - [[2-fluoro-6- (1-methylethyl) phenyl] methyl-1-methyl-1H-pyrazole-4-carboxamide from 20: 1 to 1:20 from 5: 1 to 1: 5 from 3: 1 to 1: 3 1: 1 N-cyclopropyl-3- (difluoromethyl) -5-fluoro-N - [[5-fluoro-2- (1-methylethyl) phenyl] methyl-1-methyl-1H-pyrazole-4-carboxamide from 20: 1 to 1:20 from 5: 1 to 1: 5 from 3: 1 to 1: 3 1: 1 N - [(2-cyclopentyl-5-fluorophenyl) methyl] -N-cyclopropyl-3- (difluoromethyl) -5-fluoro-1-methyl-1H-pyrazole-4-carboxamide from 20: 1 to 1:20 from 5: 1 to 1: 5 from 3: 1 to 1: 3 1: 1 N '- [2,5-dimethyl-4 - [[3- (1,1,2,2-tetrafluoroethoxy) phenyl] thio]
phenyl] -N-ethyl-N-methylmethanimidamide from 20: 1 to 1:20 from 5: 1 to 1: 5 from 3: 1 to 1: 3 1: 1 N '- [4 - [[4-chloro-3- (1,1,2,2-tetrafluoroethoxy) phenyl] thio] -2,5-dimethylphenyl] -N-ethyl-N-methylmethanimidamide from 20: 1 to 1:20 from 5: 1 to 1: 5 from 3: 1 to 1: 3 1: 1

N-ethyl-N '- [4 - [[4-fluoro-3- (1,1,2,2-tetrafluoroethoxy) phenyl] thio] -2,5-dimethylphenyl] -N-methylmethanimidamide from 20: 1 to 1:20 from 5: 1 to 1: 5 from 3: 1 to 1: 3 1: 1 N '- [2,5-dimethyl-4- [3 - [(1,1,2,2-tetrafluoroethyl) thio] phenoxy]
phenyl] -N-ethyl-N-methylmethanimidamide from 20: 1 to 1:20 from 5: 1 to 1: 5 from 3: 1 to 1: 3 1: 1 N '- [2,5-dimethyl-4- [4-chloro-3 - [(1,1,2,2-tetrafluoroethyl) thio] phenoxy]
phenyl] -N-ethyl-N-methylmethanimidamide from 20: 1 to 1:20 from 5: 1 to 1: 5 from 3: 1 to 1: 3 1: 1 N '- [2,5-dimethyl-4- [4-fluoro-3 - [(1,1,2,2-tetrafluoroethyl) thio] phenoxy]
phenyl] -N-ethyl-N-methylmethanimidamide from 20: 1 to 1:20 from 5: 1 to 1: 5 from 3: 1 to 1: 3 1: 1

N '- [2,5-dimethyl-4 - [[3- (1,1,2,2-tetrafluoroethyl) thio] phenyl] thio]
phenyl] -N-ethyl-N-methylmethanimidamide from 20: 1 to 1:20 from 5: 1 to 1: 5 from 3: 1 to 1: 3 1: 1 2- [3,5-bis (difluoromethyl) -1H-pyrazol-1-yl] -1- [4- [4- [4,5-dihydro-5- [2 - [(methylsulfonyl) oxy] phenyl] - 3-isoxazolyl] -2-thiazolyl] -1-piperidinyl] ethanone from 400: 1 to 1: 1 from 100: 1 to 4: 1 50: 1 to 8: 1 1: 1 2- [3,5-bis (difluoromethyl) -1H-pyrazol-1-yl] -1- [4- [4- [5- [2-fluoro-6 - [(methylsulfonyl) oxy] phenyl] -4, 5-dihydro-3-isoxazolyl] -2-thiazolyl] -1-piperidinyl] ethanone from 400: 1 to 1: 1 from 100: 1 to 4: 1 50: 1 to 8: 1 1: 1

2- [3,5-bis (difluoromethyl) -1H-pyrazol-1-yl] -1- [4- [4- [5- [2-chloro-6 - [(methylsulfonyl) oxy] phenyl] -4, 5-dihydro-3-isoxazolyl] -2-thiazolyl] -1-piperidinyl] ethanone from 400: 1 to 1: 1 from 100: 1 to 4: 1 50: 1 to 8: 1 1: 1 2-fluoro-6 - [(8-fluoro-2-methyl-3-quinolinyl) oxy] -α, α-dimethylbenzylmethanol 40: 1 to 1:10 from 10: 1 to 1: 3 from 5: 1 to 1: 2 1: 1 2 - [(7,8-difluoro-2-methyl-3-quinolinyl) oxy] -6-fluoro-α, α-dimethylbenzylmethanol 40: 1 to 1:10 from 10: 1 to 1: 3 from 5: 1 to 1: 2 1: 1 9-fluoro-2,3-dihydro-2,2-dimethyl-5- (3-quinolinyl) -1,4-benzoxazepine 40: 1 to 1:10 from 10: 1 to 1: 3 from 5: 1 to 1: 2 1: 1 (1R, 2S, 5S) -rel-2- (chloromethyl) -5 - [(4-chlorophenyl) methyl] -2-methyl-1- (1H-1,2,4-triazol-1-ylmethyl) cyclopentanol 40: 1 to 1:10 from 10: 1 to 1: 3 from 5: 1 to 1: 2 1: 1

1 - [[4 - [(4-chlorophenyl) methyl] -1-methyl-6-oxabicyclo [3.2.0] hept-5-yl] methyl] -1H-1,2,4-triazole 40: 1 to 1:10 from 10: 1 to 1: 3 from 5: 1 to 1: 2 1: 1 3 - [(4-chlorophenyl) methyl] -2-hydroxy-2- (1H-1,2,4-triazol-1-ylmethyl) -1,1-cyclopentanedimethanol 40: 1 to 1:10 from 10: 1 to 1: 3 from 5: 1 to 1: 2 1: 1 3- (difluoromethyl) -N- (7-fluoro-2,3-dihydro-1,1,3-trimethyl-1H-inden-4-yl) -1-methyl-1H-pyrazole-4-carboxamide from 20: 1 to 1:20 from 5: 1 to 1: 5 from 3: 1 to 1: 3 1: 1 3 - [(3,4-dichloro-5-isothiazolyl) methoxy] -1,2-benzisothiazole, 1,1-dioxide from 20: 1 to 1:20 from 5: 1 to 1: 5 from 3: 1 to 1: 3 1: 1 3- (difluoromethyl) -N-methoxy-1-methyl-N- [1-methyl-2- (2,4,6-trichlorophenyl) ethyl] -1H-pyrazole-4-carboxamide from 20: 1 to 1:20 from 5: 1 to 1: 5 from 3: 1 to 1: 3 1: 1

methyl 5H-pyrrolo [3 ', 4': 5,6] [1,4] dithiino [2,3-c] [1,2,5] thiadiazole-5,7 (6H) -dione from 20: 1 to 1:20 from 5: 1 to 1: 5 from 3: 1 to 1: 3 1: 1 3- (4,4,5-trifluoro-3,4-dihydro-3,3-dimethyl-1-isoquinolinyl) quinoline from 20: 1 to 1:20 from 5: 1 to 1: 5 from 3: 1 to 1: 3 1: 1 3- (5-fluoro-3,4-dihydro-3,3,4,4-tetramethyl-1-isoquinolinyl) quinoline from 20: 1 to 1:20 from 5: 1 to 1: 5 from 3: 1 to 1: 3 1: 1 1,1-Dimethylethyl N - [6 - [[[( Z ) - [(4,5-dihydro-4-methyl-5-oxo-1,2,4-oxadiazol-3-yl) phenylmethylene] amino] hydroxy] methyl] -2-pyridinyl] carbamate 40: 1 to 1:10 from 10: 1 to 1: 3 from 5: 1 to 1: 2 1: 1 3-butyn-1-yl N - [6 - [[[( Z ) - [(4,5-dihydro-4-methyl-5-oxo-1,2,4-oxadiazol-3-yl) phenylmethylene] amino] hydroxy] methyl] -2-pyridinyl] carbamate 40: 1 to 1:10 from 10: 1 to 1: 3 from 5: 1 to 1: 2 1: 1

Table B below shows embodiments of specific compositions containing a solid form of compound 1 (polymorphic form B) and an additional means of controlling invertebrate pests.

Table B Invertebrate Pest Control Mechanism of action or class of chemicals Typical
weight ratio Abamectin Macrocyclic lactones 50: 1 to 1:50 Acetamipride Neonicotinoids from 150: 1 to 1: 200 Amitraz Octopamine Receptor Ligands from 200: 1 to 1: 100 Avermectin Macrocyclic lactones 50: 1 to 1:50 Azadirahtin Ecdysone agonists from 100: 1 to 1: 120 Beta-cyfluthrin Sodium channel modulators from 150: 1 to 1: 200 Bifenthrin Sodium channel modulators from 100: 1 to 1:10 Buprofesin Chitin Synthesis Inhibitors 500: 1 to 1:50 Cartap Nereistoxin analogues from 100: 1 to 1: 200 Chlorantraniliprol Ryanodine receptor ligands from 100: 1 to 1: 120 Chlorfenapyr Mitochondrial Electron Transport Inhibitors from 300: 1 to 1: 200 Chlorpyrifos Cholinesterase Inhibitors from 500: 1 to 1: 200 Clothianidin Neonicotinoids from 100: 1 to 1: 400 Cyanthraniliprol Ryanodine receptor ligands from 100: 1 to 1: 120 Tsiflutrin Sodium channel modulators from 150: 1 to 1: 200 Cigalotrin Sodium channel modulators from 150: 1 to 1: 200 Cypermethrin Sodium channel modulators from 150: 1 to 1: 200 Cyromazine Chitin Synthesis Inhibitors 400: 1 to 1:50

Deltamethrin Sodium channel modulators from 50: 1 to 1: 400 Dieldrin Cyclodiene Insecticides from 200: 1 to 1: 100 Dinotefuran Neonicotinoids from 150: 1 to 1: 200 Diophenolan Molt inhibitor from 150: 1 to 1: 200 Emamectin Macrocyclic lactones 50: 1 to 1:10 Endosulfan Cyclodiene Insecticides from 200: 1 to 1: 100 Esfenvalerate Sodium channel modulators from 100: 1 to 1: 400 Etiprol GABA Controlled Chloride Channel Blockers from 200: 1 to 1: 100 Fenothiocarb from 150: 1 to 1: 200 Phenoxycarb Juvenile hormone imitators from 500: 1 to 1: 100 Fenvalerate Sodium channel modulators from 150: 1 to 1: 200 Fipronil GABA Controlled Chloride Channel Blockers from 150: 1 to 1: 100 Flonicamide from 200: 1 to 1: 100 Clubendiamide Ryanodine receptor ligands from 100: 1 to 1: 120 Flufenoxuron Chitin Synthesis Inhibitors from 200: 1 to 1: 100 Hexaflumuron Chitin Synthesis Inhibitors 300: 1 to 1:50 Hydramethylnon Mitochondrial Electron Transport Inhibitors from 150: 1 to 1: 250 Imidacloprid Neonicotinoids from 1000: 1 to 1: 1000 Indoxacarb Sodium channel modulators 200: 1 to 1:50 Lambda cygalothrin Sodium channel modulators from 50: 1 to 1: 250 Lufenuron Chitin Synthesis Inhibitors from 500: 1 to 1: 250 Metaflumizone from 200: 1 to 1: 200

Metomil Cholinesterase Inhibitors from 500: 1 to 1: 100 Metoprene Juvenile hormone imitators from 500: 1 to 1: 100 Methoxyphenoside Ecdysone agonists 50: 1 to 1:50 Nitenpiram Neonicotinoids from 150: 1 to 1: 200 Nithiazine Neonicotinoids from 150: 1 to 1: 200 Novaluron Chitin Synthesis Inhibitors from 500: 1 to 1: 150 Oxamil Cholinesterase Inhibitors from 200: 1 to 1: 200 Pymetrosine from 200: 1 to 1: 100 Pyrethrin Sodium channel modulators from 100: 1 to 1:10 Pyridaben Mitochondrial Electron Transport Inhibitors from 200: 1 to 1: 100 Pyridyl from 200: 1 to 1: 100 Pyriproxyphene Juvenile hormone imitators from 500: 1 to 1: 100 Ryanodin Ryanodine receptor ligands from 100: 1 to 1: 120 Spinetoram Macrocyclic lactones from 150: 1 to 1: 100 Spin garden Macrocyclic lactones 500: 1 to 1:10 Spirodiclofen Lipid biosynthesis inhibitors from 200: 1 to 1: 200 Spiromesifen Lipid biosynthesis inhibitors from 200: 1 to 1: 200 Tebufenoside Ecdysone agonists from 500: 1 to 1: 250 Thiacloprid Neonicotinoids from 100: 1 to 1: 200 Thiamethoxam Neonicotinoids from 1250: 1 to 1: 1000 Thiodicarb Cholinesterase Inhibitors from 500: 1 to 1: 400 Thiosultap Sodium from 150: 1 to 1: 100

Tralomethrin Sodium channel modulators from 150: 1 to 1: 200 Triazamate Cholinesterase Inhibitors from 250: 1 to 1: 100 Triflumuron Chitin Synthesis Inhibitors from 200: 1 to 1: 100 Bacillus thuringiensis Biological products 50: 1 to 1:10 Delta-endotoxin Bacillus thuringiensis Biological products 50: 1 to 1:10 NPV (e.g. Gemstar) Biological products 50: 1 to 1:10

Diseases caused by fungal pathogens are controlled in agronomic and non-agronomic routes of administration by using the solid form of compound 1 , usually in the form of a composition, in a biologically effective amount in relation to the habitat of the fungal pathogens, including the agronomic and / or non-agronomic location of the disease, in relation to the territory to be protected or directly in relation to pests to be controlled.

Thus, the present invention provides a method for protecting a plant or plant seed from diseases caused by fungal pathogens in agronomic and / or non-agronomic routes of administration, comprising applying to the plant or seed or medium in which the plant or seed contains a biologically effective amount of a solid form compounds 1, or with a composition containing at least one such compound, or with a composition containing at least one such compound and at least one additional biol a naturally active compound or agent. Examples of suitable compositions containing a solid form of compound 1 and at least one additional biologically active compound or agent include granular compositions where the additional active compound is in the same granule as the compound of the present invention, or in separate granules relative to granules with the compound according to the present invention.

Embodiments of the method of the present invention include contacting the habitat. A method should be noted where the habitat is a plant. It should also be noted a method where the habitat is an animal. It should also be noted a method where the habitat is a seed.

In order to achieve contact with the solid form of compound 1 or with the composition of the present invention to protect the field crop from diseases caused by fungal pathogens, the solid form of compound 1 or composition is usually applied to the seeds of the crop before planting, to the foliar parts (e.g. leaves, stems, flowers, fruits) of cultivated plants or to the soil or other medium for cultivation before planting or after the crop.

One embodiment of the contacting method is carried out by spraying. Alternatively, a granular composition containing a compound of the present invention can be applied to foliage of a plant or soil. Solid forms of compound 1 can also be efficiently delivered by absorption by plants upon contact with a composition containing the compound of the present invention, used as a liquid composition for wetting the soil, granular composition for the soil, when treating a seedling box or when immersing transplanted plants. It should be noted the composition of the present invention in the form of a liquid composition for soil treatment. It should also be noted a method of protecting a plant or plant seed from diseases caused by fungal pathogens, comprising the use of a biologically effective amount of a solid form of compound 1 or a composition containing a biologically effective amount in relation to the plant or seed or the environment in which the plant or seed is located solid form of compound 1 . In addition, it should be noted that the solid forms of compound 1 are also effective when applied topically to the location of the disease. Other contacting methods include the use of a solid form of compound 1 or a composition of the present invention with direct spray solutions and aftered spray solutions, aerial spray solutions, gels, seed coatings, microencapsulated preparations, systemic absorption preparations, baits, ear tags, boluses, foggers, fumigants, aerosols, dust preparations, and much more. One embodiment of the contacting method provides a non-shrink pellet, stick, or fertilizer tablet containing a solid form of compound 1 or a composition of the present invention. Solid forms of compound 1 can also be incorporated into building materials.

Solid forms of compound 1 are also useful in seed treatment methods to protect seeds from diseases caused by fungal pathogens. In the context of the present disclosure and claims, treating a seed means bringing the seed into contact with a biologically effective amount of a solid form of compound 1 , which is usually formulated as a composition of the present invention. Seed treatment protects the seed from diseases caused by fungal pathogens and, as a rule, can also protect the roots and other parts of the plant in contact with the soil around the seedling that develops from the germinating seed. Seed treatment can also provide foliage protection by transferring compound 1 or the second active ingredient to a developing plant. Seed treatment methods can be applied to all types of seeds, including those from which plants genetically transformed to express specific traits will germinate. Illustrative examples of genetically transformed plants include plants expressing proteins that are toxic to parasitic nematodes, such as the toxin Bacillus thuringiensis , or expressing proteins that confer resistance to herbicides, such as glyphosate acetyl transferase, which provides resistance to glyphosate.

One method of seed treatment is carried out by spraying onto the seeds a solid form of compound 1 (i.e., as a formulated composition) or by pollinating the seeds with it before sowing the seeds. Compositions formulated for seed treatment typically comprise a film former or an adhesive agent. Therefore, the seed coating composition of the present invention contains a biologically effective amount of a solid form of compound 1 and a film former or adhesive agent. The seeds can be coated by spraying a fluid suspension concentrate directly onto the seed layer in a tumbling drum and then drying the seeds. Alternatively, other types of formulations, such as wettable powders, solutions, suspoemulsions, emulsifiable concentrates and emulsions in water, can be sprayed onto the seeds. This method is particularly applicable to film coating of seeds. Various coating machines and methods are available to those skilled in the art. Suitable methods include those listed in P. Kosters et al., Seed Treatment: Progress and Prospects , 1994 BCPC Mongraph No. 57, and in the references therein.

The solid forms of compound 1 and their compositions, both individually and in combination with other insecticides, nematicides and fungicides, are especially applicable to the processing of seeds of agricultural crops, including, without limitation, maize or corn, soybean, cotton, cereals ( e.g. wheat, oats, barley, rye, and rice), potatoes, vegetables, and oilseed rape.

Other insecticides or nematicides with which solid formulations of compound 1 can be formulated to formulate mixtures suitable for seed treatment include, without limitation, abamectin, acetamiprid, acrinatrin, amitraz, avermectin, azadirachtin, bensultap, bifentrin, buprofesin, cadusafos, carbaril, carbofil, , cartap, chlorantraniliprol, chlorfenapyr, chlorpyrifos, clotianidin, cyanthraniliprol, cyfluthrin, beta-cyfluthrin, cygalotrin, gamma-cygalotrin, lambda-cygalotrin, cypermethrin, alpha-cypermethrin, zeta-cypermethrin, ciromazine, delta eldrin, dinotefuran, diofenolan, emamectin, endosulfan, esfenvalerate, ethiprole, etofenprox, etoxazole, fenothiocarb, fenoxycarb, fenvalerate, fipronil, flonicamid, flubendiamide, flufenoxuron, flyuvalinat, formetanat, fosthiazate, hexaflumuron, hydramethylnon, imidacloprid, indoxacarb, lufenuron, metaflumizone, methiocarb, metomil, metoprene, methoxyphenoside, nitenpyram, nithiazine, novaluron, oxamyl, pymetrosine, pyrethrin, pyridaben, pyridyl, pyriproxifen, ryanodine, spinetorams, spinosad, spirodiclofen, spiromezifen, spiret, op, tebufenozide, tetramethrin, thiacloprid, thiamethoxam, thiodicarb, thiosultap sodium, tralomethrin, triazamate, triflumuron, delta-endotoxin Bacillus thuringiensis, all strains of Bacillus thuringiensis and all strains of nuclear polyhedrosis viruses.

Fungicides with which it is possible to formulate solid forms of compound 1 to obtain mixtures suitable for seed treatment include, without limitation, amisulbrom, azoxystrobin, boscalide, carbendazim, carboxin, cymoxanil, ciproconazole, diphenoconazole, dimethomorph, fluazinam, fludioxonol, fluquinazonol, fluoxastrobin, flutriafol, fluxapiroxade, ipconazole, iprodion, metalaxyl, mefenoxam, metconazole, miklobutanil, paclobutrazole, penflufen, picoxystrobin, prothioconazole, pyraclostrobin, sedaxane, silthiofam, tibucone azole, thiophanate-methyl, thiram, trifloxystrobin and triticonazole.

Compositions containing solid forms of compound 1 suitable for seed treatment may additionally contain bacteria and fungi that are capable of providing protection against the harmful effects of plant pathogenic fungi or bacteria and / or soil animals such as nematodes. Bacteria exhibiting nematicidal properties may include, without limitation, Bacillus firmus , Bacillus cereus , Pasteuria penetrans, and Pasteuria nishizawae . A suitable strain of Bacillus firmus is CNCM strain I-1582 (GB-126), which is commercially available as BioNemTM. A suitable strain of Bacillus cereus is strain NCMM I-1592. Both Bacillus strains are disclosed in US 6406690. Other suitable bacteria exhibiting nematicidal activity are B. amyloliquefaciens IN937a and B. subtilis strain GB03. Bacteria exhibiting fungicidal properties may include, without limitation, B. pumilus strain GB34. Species of fungi exhibiting nematicidal properties may include, without limitation, Myrothecium verrucaria , Paecilomyces lilacinus, and Purpureocillium lilacinum .

Seed treatment methods may also include the use of one or more nematicidal agents of natural origin, such as an elicitor protein called harpin, which is isolated from certain bacterial plant pathogens, such as Erwinia amylovora . An example is Harpin-N-Tek seed treatment technology, available as N-Hibit ™ Gold CST.

Methods for treating seeds may also include the use of one or more types of nodule bacteria living in legumes of legumes, such as the nitrogen-fixing microsymbiont bacterium Bradyrhizobium japonicum . These inoculants may optionally contain one or more lipo-chitooligosaccharides (LCOs), which are factors in the formation of nodules (Nods) produced by nodule bacteria during the initiation of nodule formation on legumes of legumes. For example, Optimize® proprietary seed treatment technology includes LCO Promoter Technology ™ in combination with an inoculant.

Seed treatment methods may also include one or more isoflavones, which can increase the level of root colonization by mycorrhizal fungi. Mycorrhizal fungi improve plant growth by enhancing the absorption by roots of nutrients such as water, sulfates, nitrates, phosphates and metals. Examples of isoflavones include, without limitation, genistein, biochanin A, formononetin, daidzein, glycitein, hesperetin, naringenin and pratensein. Formononetin is available as an active ingredient in a product containing a mycorrhizal inoculant, such as PHC Colonize® AG.

Methods for treating seeds may also include the use of one or more activators of plant defense mechanisms that induce systemic acquired resistance in plants after contact with the pathogen. An example of an activator of plant defense mechanisms that induces such defense mechanisms is acibenzolar- S- methyl.

Treated seeds typically contain a solid form of compound 1 in an amount of from about 0.1 g to 1 kg per 100 kg of seeds (i.e., from about 0.0001 to 1% by weight of seeds before treatment). A flowable suspension formulated for seed treatment typically contains from about 0.5 to about 70% of the active ingredient, from about 0.5 to about 30% of a film-forming adhesive, from about 0.5 to about 20% of a dispersant, from 0 to about 5% thickener, 0 to about 5% pigment and / or dye, 0 to about 2% antifoam, 0 to about 1% preservative, and 0 to about 75% volatile liquid diluent.

Solid forms of compound 1 can be used without other adjuvants, but most often a composition containing one or more active ingredients with suitable carriers, diluents and surfactants will be used, possibly in combination with food, depending on the intended end use. One application method involves spraying an aqueous dispersion or a solution of a compound of the present invention based on refined oil. Combinations with aerosol oils, aerosol oil concentrates, adhesives, excipients, other solvents and synergists such as piperonyl butoxide often enhance the effectiveness of the compound. In the case of non-agronomic applications, the use of such spray solutions can be carried out from spray containers, such as a bottle, bottle or other container, either by means of a pump or by releasing them from a container under pressure, for example, from an aerosol spray bottle. Such sprayable compositions may take various forms, for example, sprayable solutions, fine spray formulations, foams, fumes or fogs. Such sprayable compositions may thus further comprise spraying agents, blowing agents, and the like, necessary for use. It should be noted sprayable composition containing a biologically effective amount of a solid form of compound 1 or its composition and a carrier. One embodiment of such a sprayable composition comprises a biologically effective amount of a solid form of compound 1 or a composition thereof and a spraying agent. Typical nebulizing agents include, but are not limited to, methane, ethane, propane, butane, isobutane, butene, pentane, isopentane, neopentane, pentene, hydrogen fluorocarbons, chlorine fluorocarbons, dimethyl ether, and mixtures of the above.

Despite the fact that the sprayed composition is obtained by dilution with water, a sufficient concentration of the fungicidal composition in accordance with the present invention can provide sufficient control effectiveness of fungal pathogens, while separately formulated auxiliary products can also be added to sprayable tank mixtures. These additional adjuvants are commonly known as “spray aid” or “tank mix aid” and include any substance added to the mixture in the spray tank to improve the action of the pesticide or change the physical properties of the spray mixture. Auxiliary agents can be anionic or nonionic surfactants, emulsifying agents, petroleum-based vegetable oils, seed-derived vegetable oils, acidifying agents, buffers, thickeners or anti-foaming agents. Auxiliary agents are used to increase efficiency (e.g., bioavailability, adhesion, penetration, uniformity of coating and durability of protection) or to minimize or eliminate spraying problems associated with incompatibility, foaming, drift, evaporation, volatility and decomposition. For optimal effectiveness, adjuvants are selected based on the properties of the active ingredient, formulation and purpose (e.g., crops, pests).

The amount of adjuvants added to the sprayed mixtures is usually in the range of about 2.5% to 0.1% by volume. Application rates of adjuvants added to the sprayed mixtures are typically from about 1 to 5 liters per hectare. Typical examples of sprayable adjuvants include: 47% Adigor ^® methyl rapeseed oil in liquid hydrocarbons (from Syngenta), Silwet ^® polyalkylene oxide-modified heptamethyltrisiloxane (from Helena Chemical Company) and a 17% surfactant mixture with 83% paraffin mineral oil Assist ^® (from BASF).

Non-agronomic uses relate to protecting a plant or plant seed from diseases caused by fungal pathogens in areas other than agricultural fields. Non-agronomic uses of the compounds and compositions of the present invention include the control of diseases caused by fungal pathogens in stored grains, beans or other food products, as well as in textiles or building materials. Non-agronomic uses of the solid forms and compositions of the present invention also include controlling fungal pathogens on ornamental plants, forests, gardens, along roadsides and railway tracks, and on turfs such as lawns, golf courses, and grasslands. Non-agronomic uses of the compounds and compositions of the present invention also include controlling fungal pathogens in buildings and other structures that can be populated by humans and / or domestic, agricultural, farm, zoo or other animals.

The solid forms of compound 1 are also suitable for treating plant propagation material other than seeds, such as fruits, tubers or plant seedlings. The propagation material can be treated with compounds before planting, or the compounds can be applied to the planting site when planting the propagation material.

In the case of agronomic routes of application, the rate of application necessary for effective control (ie, “biologically effective amount”) will depend on factors such as the specific types of fungal pathogens to be controlled, stage of fungus development, degree of disease, location, season host culture, ambient humidity, temperature, and the like. Under normal conditions, application rates of approximately 0.01 to 2 kg of active ingredients per hectare are sufficient to control diseases caused by fungal pathogens in agronomic ecosystems, but only 0.0001 kg / hectare may be sufficient, or at least 8 kg / hectare may be necessary . For non-agronomic applications, effective operating costs will range from about 1.0 to 50 mg / square meter, but just 0.1 mg / square meter may be sufficient, or at least 150 mg / square meter may be needed. One of skill in the art can easily determine the biologically effective amount required for the required level of control of diseases caused by fungal pathogens.

Claims (18)

1. Polymorph 4- (2-bromo-4-fluorophenyl) - N - (2-chloro-6-fluorophenyl) -1,3-dimethyl-1 H -pyrazol-5-amine, called Form B, characterized by a powder X-ray diffraction pattern in Cu (Kα1) at room temperature having at least diffraction peaks at 2θ angles 2θ
2θ
10,894 24,285 15,361 25.84 16,134 27.54 17,718 29,449 20,322 2. Polymorph 4- (2-bromo-4-fluorophenyl) - N - (2-chloro-6-fluorophenyl) -1,3-dimethyl-1 H -pyrazol-5-amine, called Form A, characterized by a powder X-ray diffraction pattern in Cu (Kα1) at room temperature having at least diffraction peaks at 2θ angles 2θ
2θ
6,395 22.23 12,668 23,885 14,507 24,919 14,99 26.34 18,984 3. A method of obtaining a polymorphic form B according to claim 1, comprising forming a suspension with a solvent of one or more solid forms of 4- (2-bromo-4-fluorophenyl) - N - (2-chloro-6-fluorophenyl) -1,3 -dimethyl-1 H -pyrazol-5-amine selected from the group of Form A, amorphous forms and mixtures of any of the above, with Form B and maintaining a suspension during the conversion of solid forms 4- (2-bromo-4-fluorophenyl) - N - (2-chloro-6-fluorophenyl) -1,3-dimethyl-1 H -pyrazol-5-amine into polymorphic form B. 4. The method according to claim 3, where the solid forms of 4- (2-bromo-4-fluorophenyl) - N - (2-chloro-6-fluorophenyl) -1,3-dimethyl-1 H -pyrazol-5-amine contain polymorphic form A. 5. The method according to claim 3, where the solid forms of 4- (2-bromo-4-fluorophenyl) - N - (2-chloro-6-fluorophenyl) -1,3-dimethyl-1 H -pyrazol-5-amine contain a mixture of polymorphs of form A and form B. 6. The method according to p. 3, where the seed crystals of polymorphic form In p. 1 is added to the suspension. 7. The method according to p. 3, where the suspension is mixed. 8. The method of claim 3, wherein the solvent comprises one or more compounds of water, a C ₄ -C ₈ ester, a C ₁ -C ₄ alkanol, a C ₃ -C ₈ ketone, a C ₄ -C ₈ ester, a C ₂ - C ₇ nitrile or aromatic C ₇ -C ₉ hydrocarbon. 9. The method of claim 8, wherein the solvent comprises one or more compounds of water or methanol. 10. The method for producing the polymorphic Form B according to claim 1, comprising (A) contacting 1- (2-bromo-4-fluorophenyl) -2-propanone and 1-chloro-3-fluoro-2-isothiocyanatobenzene in the presence of a first solvent to form a reaction mixture containing a thioamide intermediate, (B) optionally isolating a thioamide intermediate, (C) contacting the thioamide intermediate with methyl hydrazine in the presence of a second solvent to form a reaction mixture containing 4- (2-bromo-4-fluorophenyl ) - N - (2-chloro-6-fluorophenyl) -1,3-di etil-1 H -pyrazol-5-amine, and (D) crystallizing 4- (2-bromo-4-fluorophenyl) - N - (2-chloro-6-fluorophenyl) -1,3-dimethyl-1 H -pyrazole -5-amine as a polymorphic form B. 11. The method according to p. 10, where in stage (D), compound 1 is crystallized in the presence of seed crystals of polymorphic form B. 12. The method according to p. 10, where in stage (D), compound 1 is crystallized in the presence of a third solvent and seed crystals of polymorphic form B. 13. The method of claim 12, wherein the third solvent comprises one or both of water or methanol. 14. A composition for protecting a plant or plant seed from diseases caused by fungal pathogens, comprising (a) the polymorphic form B of claim 1 and (b) at least one additional component selected from the group consisting of surfactants, solid thinners and liquid carriers. 15. A composition for protecting a plant or plant seed from diseases caused by fungal pathogens, comprising (a) the polymorphic form B of claim 1 and (b) at least one other nematicide, insecticide and / or fungicide. 16. A method of protecting a plant or plant seed from diseases caused by fungal pathogens, comprising applying to the plant, or the seed, or the environment in which the plant or seed is located, a biologically effective amount of polymorphic form B according to claim 1.

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